How Maternal High Fat Diet Causes Cardiovascular Disease Biology Essay

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Overweight and obesity cause a major risk for chronic diseases such as hypertension, stroke, cardiovascular disease and cancer. Enhanced consumption of high saturated fats, sugar and nutrition poor diet and lack of physical activities is the key to the development of cardiovascular disease (2). In UK last 13 years there was 10% raise in the amount of individuals in recent times detected with type 2 diabetes were also obese (7). However latest finding put forward that throughout fetal life the cells and tissues under goes critical periods of development (2). At this critical development rapid cell division take place which uses oxygen and nutrition. Insufficient nutrition causes the fetus to adapt to low level of nutrient which slows down the cell division as a result the fetus permanently changes their structure and function of body. Thus changes cause number of chronic disease later in life such as cardiovascular disease (2). This paper will study the experiments which were done on both animals and human which compare the high fat diet fed dam's offspring with the controlled diet fed dam's fetus.


For the last 15 years it has been suggested that the adult disease such as cardiovascular disease on set by the influence of intrauterine environment during the critical period of fetus development. This evidence by the study which carried out by David Barker in 1995 which suggested that "The fetal origins hypothesis states that fetal under nutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease" (12). For a long period of time it has been proposed that cardiovascular disease is on set by the adult life style such as smoking and fat diet etc. However the Barkers hypothesis and other study have demonstrated that fetus development in the uterus has more effect in developing cardiovascular disease than adult life style.

Sufficient supply of nutrients and oxygen is the key to the intrauterine environment which regularly sets boundaries to fetal growth and weight (2). Recent experimental study of animal crossbreeding by D J P Barker (1997) demonstrated that the fetus birth weight is determined by the "intrauterine environment rather than fetus genome" (2). Nutrition is one of the factors which affect fetal programming during pregnancy (2, 3). The signs of low nutrition in the uterus are the low birth weight, placental weight, length and imbalance of head circumference at particular period of development of fetus. Daily intake and storage of nutrient of the dams, the nutrient that distributed to placenta and its ability to transport nutrient to fetus determine the fetal nutrition (2).

Consumption of HFD during pregnancy and lactation affects fetus metabolism (5). Studies which were done on animals concluded that the human body can be programmed by manipulating the dams' inter-uterine environment during crucial period of development (2). Thus particular changes in uterus during crucial period of growth cause continuing changes in fetus structure and function. This programming of the fetus determines their adulthood diseases. Many metabolic syndromes such as cardiovascular disease, diabetes mellitus, hypertension and obesity originate by the changes in the inter-uterine environment (2, 3, and 6).

As well as under nutrition, high nutrition supply could furthermore programme the fetus to develop type 2 diabetes and cardiovascular disease later in their life (6). Thereby unbalanced diet (HFD) during pregnancy will have an adverse effect on fetal programming. In developing countries nutritional imbalance is generally recognized as consuming too much fat (3). The fetus adapts to High fat ingestion by the dams during critical period of development which leads to the susceptibility to cardiovascular disease. Also vascular dysfunction of the maternal uterine artery may possibly add to the cardiac dysfunction in the fetus of the high fat diet fed dams (3).

In human the intake of high fat diet is linked to the cardiovascular disease which caused by the activation of endothelial cell and also by a reduced amount of production of endothelium derived dilators (3). Endothelium derived dilators also add to the vasodilatation of the uterine artery, maintenance of placental blood flow and vascular remodelling. Insufficient blood flow to the placenta effects the development and growth of the fetus which interns programme the fetus to develop disorders in their adulthood (3). Also oxidative stress plays important role in cardiovascular disease by increasing the production of reactive oxygen species in the vascular cells (19). In spite of development the life style during adulthood including consumption of high fat food, lack of exercise, alcohol consumption and smoking also causes of metabolic syndrome.

This essay will examine how the effect of maternal high fat diet (HFD) on offspring such as endothelial dysfunction, insulin resistance, changes in blood pressure, obese and diabetes mellitus etc all together contribute to the development of the cardiovascular disease in adult life. Rat modules studies will be analysed to indicate the effect of maternal HFD on fetus growth and adulthood disease. Few human studies are also used as evidence in this essay however most of the evidence used in this are rats because it's easy to control their diet to observe the effect of HFD.

The mother

Two different groups of rat studies were used for this review. One group of pregnant rats were fed with saturated fatty acid ((SFA) equal to the diet eaten by pregnant women in develop countries/ unbalance nutrition diet) which were also called the HFD (some studies stated as high lipid (HL)) dams and the other group of pregnant rats were fed balance diet (polyunsaturated fatty acid (PUFA)) which were also called the control dams (some studies stated as low lipid (LL)).

It has been suggested that mothers dietary intake (low nutrition/ HFD) during pregnancy has consequence on the fetus development but the HFD intake has no effect on the mother in term of weight change (the body weight between the two group was similar) (3). It has been also suggested that the mother's diet programmes the intrauterine environment which in turn programmes the fetus and thus lead to the changes in adult life such as development of the adulthood diseases (cardiovascular disease) (3).

The study by P. D. Taylor et al (2003) evidenced that the daily intake of food by the HFD dams was lower than that of control dams (3). According to this study the daily consumption of control rat between days 0 to 20 was 25.3 ± 0.66g per day and daily intake of HFD rat at same period was 19.82 ± 0.60g per day (3). As a result of this variance in daily food consumption the energy consumption by both groups was parallel. However the daily intake of fat by the HFD dams is tend to be 20% greater than the control dams (3). Both groups tend to have similar increase in body weight during pregnancy (3, 4). Table 1 below also evidenced that the both group of dams had similar weight.

Table 1: shows maternal body weight of pregnant rats fed LL diet and a HL diet.

Image from Del Prado et al (1995)

The High Lipid diet (HL) also called HFD.

The Low Lipid diet (LL) also called control diet.

This image shows that both group of rats had similar increase in body weight from day 1 to 21 of pregnancy.

During pregnancy high concentration of the plasma corticosterone and plasma insulin were detected in HFD dams than control group (3). This increased level of the hormones could be one of the reasons why the HFD dam had grater fat deposit. The high level of corticosterone causes the raise in insulin level as a result the high level of insulin in the body means that the body fat is not used up so intake of more fat food would store the fat in the body (3).

Compared to the controlled dam the HFD dams had bigger spleens which cause distorted immune function (3). Deposit of Fatty acid on the immune cell alters the inflammatory mediators which fed to the fetus and as a result the fetus develops insulin resistance, distorted sex hormone and enhanced fat deposition during adult life (3).

Effects of maternal HFD on fetus

Dams who consume HFD during pregnancy change the intrauterine environment which causes their offspring to adapt to the environment and as a result the offspring develop diseases later in their life. Dams who consumed HFD change the fetus' physiology which means fetus were born with lower weight, height and smaller placentas (3).

Fetus Growth

It has been suggested that there is a relationship between the fetus growth and development of cardiovascular disease in adult life (6, 22). This statement is evidenced by the study which was carried out in both male and female which shows that fetus that were born small had more tendency for the development of adulthood disease compared to normal fetus (22).

Poor supply of maternal nutrition is the key factor that results in delay of fetal growth, thus link to the programming of the fetus (6). As the Barker statement suggest the growth rate is one of the factors which cause coronary heart disease (22). In 1997 Barker carried out a study in Sheffield which also evidence that people who had low growth rate at birth also have enhanced risk of the coronary heart disease (2). The growth of People who were exposed to high fat environment in uterus was lower than that of control diet and those who continue to be exposed to the same environment in childhood and adulthood will contribute to disease in later life. As well as the environment of the intrauterine the adult daily life also adds to the effects (2).

Protein availability establishes the fetal growth. Insulin is a growth hormone which aid in the fetal growth. As amino acids cause insulin secretion from pancreatic beta cells, protein is an essential factor which helps fetal growth (6). This could be the reason why the HFD dam's fetus born with low growth rate compared to the control. The IGF-1 (insulin like growth factor 1) plays major role in controlling fetal growth, which is regulated by the supply of nutrition. An experiment which was done on sheep evidence that when IGF-1 had been given to the sheep increased level of amino acids and glucose was taken in by the placenta and promoted glucose delivery to the fetus (6). This could help to alter the growth rate of the sheep which in turn would have a desirable effect on the development of the diseases.

Fetus Weight

It has been proposed that reduced level of prenatal nutrition causes low birth weight in offspring and the fetus was thin until the age of two years and gained weight afterwards and thus causes the coronary heart disease in adult life (6, 22). There are three lines of evidence that support this. Firstly several studies which were done on rat's evidence that the HFD dam's fetus had low birth weight than control dam's fetus (3, 4, 5, 1, and 8). Low birth weight is one of the other factors which cause coronary heart disease, diabetes, hypertension and death by stoke in adulthood (2, 6).

Secondly another recent study in US and South India established the association between coronary disease and reduced birth weights (2). This study was done in group of men and women showed that 15% of people who weighed 2.5kg at birth were affected by coronary heart disease where as only 4% of people who weighed 3.2kg or more were affected by the disease (2). The third study which was carried out by D J P Barker (1997) showed that "the trends in coronary heart disease with birth weight have been found to be paralleled by similar trends in two of its major risk factors- hypertension and non-insulin dependent diabetes mellitus" (2).

However some studies state that there was no difference of birth weight found between the fetus of HFD dams compared to the control dams which does not support the relationship between the fetus weight and development of coronary heart disease in adult life (1, 3, and 4). There was no difference found in the weight of fetus in the early development between two groups (HFD group and LFD group) but the fetus body weight changed at 20 days of gestation, fetus of HFD dams had lower body weight than the controlled dams (3). Therefore the pups of HFD dams had low birth weight compared to the controlled dams' pups. The fetus of the HFD dams put on weight quickly since the day six of lactation and had considerably elevated weight than control fetus which also supports Barker's hypothesis (4). Therefore the change in environment after birth lead the fetus to gain weight which as a results lead to the development of cardiovascular disease later in life.

Saturated fatty acids (SFA) and Polyunsaturated fatty acids (PUFA)

It has been proposed that there is a connection between the increased intake of SFA during pregnancy and reduced hepatic LDL-r mRNA expression in relation to the elevated level of LDL cholesterol (10). This is evidence by the study which was carried out by Chechi and cheema et al (2006) which showed that the fetus fed SFA during gestation had no effect on plasma cholesterol level but the fetus that fed SFA during gestation had elevated level of total plasma cholesterol (10). On the other hand when the fetus was fed with PUFA during gestation and suckling has been shown to have decreased level of total plasma cholesterol. Therefore this experimental results evidence that the increased level of SFA intake during gestation, suckling and post weaning periods increase the risk of cardiovascular dysfunctions however elevated level of PUFA intake during this period prevents or decreases cardiovascular dysfunctions (9, 10). This is because the SFA tent to increase the concentration of LDL cholesterol in plasma where as the PUFA tent to decreases the concentration of LDL cholesterol by the increased production of HDL. Proportion of the HDL and LDL cholesterol is the factors which has influence on the cardiovascular health.


Saturated fatty acids (SFA) suggested having harmful effect on the cardiovascular health (9). The elevated level of SFA intake through HFD could also influences other metabolic disorder such as insulin resistance, dyslipidemia and hypertension as well as cardiovascular diseases in the adult offspring (1, 8). This evidence by several studies in which the fetus fed with high amount of SFA diet during pregnancy and suckling developed vascular dysfunctions, dyslipidemia and unusual composition of fatty acid (8, 9, and 10). The mechanisms for these effects are not identified. The HFD which is rich in SFA causes abnormalities in plasma lipids which lead to the development of the endothelial dysfunction (10). High SFA during gestation and postnatal period also causes vascular dysfunction, aorta fatty acid and plasma lipid abnormalities in the adult fetus (1, 10). Thus abnormalities are the early sings for the development of cardiovascular disease (1).

Also the increase intake of SFA during gestation and suckling periods showed that the contraction of the aorta is significantly reduced compared to the controlled offspring (10). When the contractile response to KCl was measured in the female, the offspring fed with SFA/SFA, SFA/LFD and LFD/SFA showed that the contraction was reduced by 45% compared to the fetus fed with LFD/LFD (8, 10). When this was monitored in the male offspring the result showed that the fetus fed with SFA had 50% reduction in contractile response compared to the fetus fed with control diet. Thus result proves that the fetus exposed to SFA during their development would develop reduce contractile response to the aorta (9, 10).

Experimental evidence shows that the SFA is tend to increased in fetus of HFD dams aorta than control offspring (8, 9). Thus increased level of SFA causes the plasma LDL cholesterol concentration to increase in the blood (9). Several studies evidenced that the LDL cholesterol concentration have been suggested to be elevated in a group of fetus which were fed with HFD/HFD (prenatal/postnatal) and LFD/HFD compared to the fetus fed with HFD/LFD and LFD/LFD (9, 10). However other studies showed that the concentration of LDL cholesterol was elevated in the fetus fed with HFD/LFD than LFD/LFD (1, 8, and 10). Thus shows that increased intake of HFD during prenatal and postnatal period increase the concentration of SFA which in turn raises the concentration of LDL concentration in the plasma (Figure: - 3).

The LDL cholesterol is causes harmful to cardiovascular function; elevated level of LDL cholesterol builds up in the vascular walls or reacts with oxygen which in turn causes cardiovascular dysfunction such as atherosclerosis (9). The elevated level of LDL builds up in the aortic walls in a form of oxidized LDL as they react to the reactive oxygen species (9, 10). The elevated levels of SFA also promote free radical synthesis which aid in the vascular dysfunction by declining the production of endothelium derived vasodilators such as NO (Figure: - 1) (10). Plasma concentration of lipoprotein such as triglycerides (TG) were increased in the SFA/SFA, SFA/control and control/SFA fetus compared to the control/control offspring (9, 10). Thus shows that raised concentration of SFA has harmful effects on the prenatal and postnatal period of the fetus (Figure 4C).





Cardiovascular dysfunction

Figure: - 1 shows how elevated saturated fatty acid causes cardiovascular dysfunction

SFA and Liver

Increased intake of SFA causes the raise of LDL cholesterol in the plasma and it also inhibits the hepatic LDL receptor (LDL-r) expression (10). The hepatic LDL-r helps to regulate LDL cholesterol by removing it from the blood which aid in the healthy circulation of the heart. Several experimental studies evidence suggested that female offspring exposed to HFD during prenatal and postnatal life had reduced expression of hepatic LDL-r mRNA in the liver (10). Thus reduction of LDL-r in female offspring could increase the LDL cholesterol concentration in circulation which in turn may cause cardiovascular problems. However there was no evidence of difference found among the male fetus between high fat diet and control diet for the mRNA expression of hepatic LDL-r. Whereas in the female offspring the SFA/control had 30% reduction of mRNA expression of LDL-r when compared with female control fetus (10). This shows that the effect of SFA could be gender specific.

Figure: - 2. Shows the expression of mRNA of hepatic LDL-r in the liver of male and female offspring

This diagram is obtained from Kanta Cheechi et al (2009)

In the male offspring there was not much difference found in the expression of hepatic LDL-r mRNA among each the group of SFA and control diet. Only in the group of C/S expression of LDL-r mRNA reduction was detected. However in female offspring there was huge difference found in the expression of hepatic LDL-r mRNA in the S/S group compared to control. Expression of hepatic LDL- r mRNA in S/C is reduced compared to C/C but offspring exposed to C/S is much more reduced than S/C fed offspring.


Polyunsaturated fatty acids (PUFA) comprise a defensive effect on cardiovascular health (9). Increased levels of PUFA tend to lower the total plasma cholesterol concentration (9). Increased level of PUFA also increases HDL cholesterol (Figure 4D). The elevated levels of HDL have been suggested to control the LDL cholesterol concentration and therefore improving cardiovascular functions. Several studies demonstrated that the fetus dams fed with control diet had high level of PUFA than those fed with HFD (8, 9, and 10). Thus proves that the both prenatal and postnatal PUFA diet of the fetus has important function of protecting the cardiovascular health (Figure: - 3).

Figure: - 3 shows how PUFA improves cardiovascular dysfunction

Improves cardiovascular function






Figure: - 4. Concentration of cholesterol in the plasma of male female offspring

The image obtained from Kata Chechi et al (2009)

This shows concentration of different type of cholesterol such as TG (Figure 4A), total cholesterol (Figure 4B), LDL-C (Figure 4C), HDL-C (Figure 4D) and ratio of LDL/HDL cholesterol (Figure 4E) in the plasma of female and male offspring. In this diagram S/S shows the intake of saturated fatty acid in both prenatal and postnatal periods by the fetus, S/C shows the intake of saturated fatty acid during prenatal period and controlled diet during postnatal period, C/C shows fetus intake of controlled diet during both periods and C/S shows the fetal intake of control diet during prenatal period and saturated fatty acid during prost natal period. Figure 4A shows that in both female and male the intake of SFA in prenatal period increased the concentration of TG compared to controlled offspring. The concentration of TG during postnatal period also increased compared to control but when compared to prenatal period the level of elevated TG is less in postnatal period. Figure 4B shows that the concentration of total cholesterol had opposite effect to the TG concentration in plasma. The total cholesterol concentration is increased in the prenatal period compared to control but it's not increased as well as during the intake of SFA in postnatal period. Figure 4C shows that LDL-C concentration was elevated during S/S and C/S period in both fetus compared to C/C and S/C period. Figure 4D shows that in male fetus the concentration of HDL-C was elevated compared to control but in female there was no difference. In both fetuses the concentration of HDL-C was increased during S/C compared to control but not as well as during C/S period. Figure 4E shows that in male the ratio of LDL/HDL concentration was increases during S/S compared to control but in female offspring the ratio during S/S was more increased compared to the male during the same period. The ratio during S/C in female increased compared to male. The ratio during C/S was elevated in both fetus compared to control.

Arachidonic acid (AA) and docosahexaenic acid (DHA)

Arachidonic acids (AA) and docosahexaenic acid are members of PUFA. In vascular smooth muscle and endothelium AA and DHA said to be the main components of plasma membrane. AA is a vasoactive substance, by inhibiting the delay of K current and opening Ca2+ activated K channels it promotes vasodilatation (1).

DHA is said to be anti-arrhythmic and cardio-protective and it also reduce endothelial cell vulnerability to oxidative stimuli (1, 21). The vascular endothelial cells membrane fluidity is affected by the DHA (1). Reduced level of DHA is found in the fetus of HFD fed dams, thus a reduction changes vascular endothelial cell function. The reduction of DHA occurs in the fetus of HFD fed dams due to the competition between SFA and DHA to transfer through the placenta. As the concentration of SFA is high in the blood of the fetus of HFD fed dam compared to DHA increased level of SFA is transferred through the placenta (1, 21). Therefore reduced level of DHA is detected in the liver of the newborn of HFD fed dams. Thus reduced concentration of offspring DHA causes permanent changes in the membrane protein and these changes averts typical docking with DHA including molecular species (1).

Linoleic (n-6/ omega-6) and alpha linoleic acids (n-3/ omega-3) give rise to AA and DHA correspondingly by the process of desaturation (1). The fatty acid enzyme activity is programmed by the HFD. Therefore HFD causes abnormal desaturation of the fatty acids which in turn reduce the concentration of AA and DHA. Thus changes have an effect on an assortment of enzyme that occupy in metabolism. This essential fatty acids (AA and DHA) reduction is also seen in the patient with diabetes which related with the problems of vasculature (1, 21).

Endothelial dysfunction

Recent studies have recognised that the endothelial dysfunction has influence on the enhanced risk of cardiovascular diseases. In human the HFD intake leads to the activation of the endothelial cell and decrease production of endothelium derived dilators (3). The last 40 years studies of epidemiology have established an association between high fat diet and health and disease. In developing country the modern life style lead to the intake of high fat food and combination of reduced physical activity have harmful effect on cardiovascular health (3, 1, 8). In analysis of HFD during gestation and suckling for cardiovascular disease, several studies revealed that the HFD during gestation is critical time for the development of cardiovascular disease, but a number of studies state the suckling stage as critical period for the development of the cardiovascular dysfunction in later life (3, 1, and 8).

A study which was carried out by M. A. Hanson et al (2004) showed that the high fat diet intake strongly predict the vascular endothelial dysfunction this is proved by the study of Joanne L. Rodford et al (2008). To test this M.A Hanson et al had demonstrated an experiment in which they had fed one rat with the high fat diet and other with the control diet. Then they took two pubs from each group and fed half with the same as mothers' diet in which they assume the offspring would have predicted the diet. The other group was fed with different diet to mother postnatal so the fetus would have been predicted the mothers diet but they were given different diet which lead to the development of the cardiovascular disease and other metabolic dysfunction in later life (8). This provides evidence for the predictive adaptive response hypothesis which suggests that there is mismatch among the prenatal environment and the future environment which is predicted by the offspring. By isolating the endothelium this study showed that the HFD during gestation and suckling increase vascular endothelial dysfunction (8).

P. Ghosh et al (2001) study demonstrated that the 15 and 60 day old fetus of dams fed saturated fatty acids (SFA) during gestation developed altered plasma lipid and vascular dysfunction, also the 1 and 15 days old offspring showed abnormalities in the fatty acid composition in the liver (1). Thus generation of the vascular endothelial impaired function is one of the mechanisms in which the concentration of lipids in the blood increases this leads to the coronary heart disease, atherosclerosis and other metabolic dysfunction.

The HFD during pregnancy and suckling have been suggested to increase circulating lipoprotein particles such as low density lipoprotein (LDL), triglyceride ((TG) (P < 0.5)), and reduce high density lipoprotein ((HDL) (P< 0.05)) than control, which linked to the endothelial dysfunction as a consequence coronary heart disease occurs (1, 8, 9,11). These lipoproteins were called circulating atherogenic lipoproteins. As vascular endothelium comes in contact with that harmful atherogenic lipoprotein coronary artery dysfunctions occurs (13).

These harmful lipoproteins also cause atherosclerosis of arteries which eventually lead to heart attack and death (13). The increased level of the TG (Figure 4A) in the blood cholesterol in the adult offspring of HFD fed dams associated with the development and severity of atherosclerosis. Thus high level of fat food cause thickening of the coronary artery by the elevated level of TG. If the level of the TG would reduce then atherosclerosis only slowly progressed this is proved by Ericsson CG et al (1996) (14). This establishes why HFD offspring most likely to develop coronary dysfunction than control offspring.

Endothelial - dependent relaxation

Several studies have revealed that HFD affect endothelial-dependent relaxation (1, 8). Arteries of 160 days old offspring of HFD dams showed decrease relaxation which is induce by acetylcholine (ACh) (1). This evidence that the offspring exposed to HFD during gestation or suckling reveal relaxation induced by acetylcholine compared to control offspring (1, 11). However there was no difference found in the sensitivity to ACh in both groups, this is due to the similarity of pEC50 values in both groups (1, 8). This response of acetylcholine in endothelium dependant relaxation thought to give rise to the variety of coronary dysfunction (1, 11). For example HFD fed dams' 160 days old fetus femoral artery developed impaired relation which was induced by acetylcholine (1). HFD fed dams also shown an impaired relaxation response to acetylcholine in mesenteric artery (3, 8). This suggests that the mesenteric artery of fetus of HFD fed mother undergoes endothelial dysfunction which also causes systolic blood pressure to increase (SBP) (8).

These impaired responses are caused by the reduction of Nitric oxide (NO), prostacyclin and endothelium derived hyperpolarising features which are concerned by the acetylcholine induced vasodilatation (1). Vascular endothelium manages vascular tone by releasing vasoconstrictor substance such as endothelin, thromboxane A2 and free radicals and vasodilator substance for instance prostacyclin and NO (1, 13). NO production is stimulated by bradykinin, thrombin, adenosine diphosphate, substance P, histamine and acetylcholine. NO is formed by the action of endothelial nitric oxide syntheses (eNOS) on the amino acid L-arginine. The NO aid in vasodilatation by diffusing to vascular smooth muscle and causing the guanylate cyclase to activate which in sequence causes the rise of cGMP (17).

Damaged endothelium-dependent dilatation is primary aspect of atherosclerosis which is caused by the reduced production of NO which in turn increases homocysteine, prostacyclin, cholesterol and blood pressure (3, 1, and 13). Experimental evidence shows that the fetus of HFD fed dams blood pressure was elevated in 180 day which indicates that blood pressure was elevated as a result of reduced level of NO production (3). NO inhibit platelet aggregation therefore serves as anticoagulation. It also inhibits neurophill endothelial interaction is antimitogenic to vascular smooth muscle and promotes recovery of endothelium from injury.

HFD fed offspring during postnatal period had increased level of reduced relaxation in reaction to ACh compared to HFD fed offspring during prenatal period. This suggests that the postnatal endothelium is more vulnerable. In all form of cardiovascular disease endothelial NO system is impaired as a result its considered as the early sign of the damaging effect of a disease of vascular system. Therefore the increased intake of HFD reduces NO production which in turn induces endothelial dysfunctions by causing the vasculature to become prospasmodic, prothromboic and proathrognic as a results of this coronary dysfunction occur (15).

Oxidative stress and endothelial dysfunction

Several studies have evidence that the HFD fed dams fetus develops oxidative stress in response to reduce level of NO which also thought to cause vascular dysfunction (1, 16). A number of experimental evidences also shows that the by supporting endothelial dysfunction the oxidative stress causes atherogenesis (1, 16, 17, 19). Production of NO depends on the endothelial cell NO synthase (eNOS) and also inactivation by the reactive oxygen species (ROS) for example superoxide anion (18, 19).

Increased level of oxidative stress in the body causes cardiovascular disease such as hypercholesterolaemia, hypertension, heart failure, atherosclerosis and type II diabetes (18, 19, and 20). As a result of elevated level of oxidative stress increased amounts of reactive oxygen species (ROS) such as superoxide anion (O2−), hydroxyl radical, lipid radicals and H2O2 are formed in the vascular cells (19).

We all need oxygen to stay alive however too much of oxygen may possibly cause damage to cells. 90% of oxygen we use is used by the mitochondria to produce ATP by oxidative phosphorylation as need by the cells for survival. Therefore it's essential but it can be problematic. If the pressure of oxygen or the concentration oxygen is increased then the cells system cannot hope with that amount of oxygen so creates problems. This associate with damage to enzymes such as xanthine oxidases (XO) and nicotinamide adenine dinucleotide (phosphate) (NADH/NAD(P)H) oxidases by oxygen (19). The oxygen causes this damage to enzyme by oxidative reduction which produces superoxide. Superoxide anion (O2−) is a free radical which causes oxidative stress (18, 19).

O2− is an important molecule which aid in the formation of other ROS as a result of the reaction of O2. The primary sources of the ROS in the vasculatures are the xanthine oxidases, mitochondrial respiratory chain, NAD (P) H oxidases and uncoupled endothelial nitric oxide syntheses (eNOS) (16, 18, and 20). The principal source of O2− is NAD (P) H oxidase in the vascular cell. During oxidation atherogenic stimuli activated NAD (P) H and induce angiotensin II (Ang II) and LDL. Under certain circumstance the neuronal NOS (nNOS) and eNOS produce O2− rather than NO (20).

Increased oxidative stress in the vasculature causes to O2− increase as a result the O2− and other free radicals react with NO which causes endothelial dysfunction (Figure: - 5). Peroxynitrite is produce by the reaction of NO and O2− which is an oxidant that provoke oxidation of lipids and proteins (19, 20). Also the ROS can stimulate vascular inflammation which could lead to the building up of plaque in the vascular walls as a consequences cardiovascular disease such as atherosclerosis occurs (18, 19, and 20).

Elevated level of ROS production leads the impaired function of endothelium dependent dilation of arteries (16, 19). This review showed that the impaired endothelium dysfunction is caused by the reduce level of NO or loss of activity of NO on the vascular walls. This reduction of NO could be caused by the reduce expression of eNOS or by the degradation of NO by ROS (18). In HFD fetus the level of superoxide is increased which causes the reduce production of NO and in turn produce endothelial dysfunction (16, 18, 19). Therefore these finding put forward that HFD promotes oxidative stress which in turn produce vascular endothelial dysfunctions.

HFD elevates the production of LDL which is oxidized (Ox-LDL) by the oxidative stress that produce during the reduction of NO. This Ox-LDL could cause endothelial dysfunction as the Ox-LDL aid in the inhibition of L-arginine up take by the endothelial cells which causes the reduced generation NO and as a result of this cardiovascular dysfunction occur (16, 17, 18, 19).

Oxidative stress and type 2 diabetes

The fetus with type 2 diabetes mellitus (T2DM) when consuming HFD develops endothelial dysfunction and also oxidative stress increases compared with healthy control offspring (13). As found out earlier the oxidative stress caused by the reduced concentration of HDL cholesterol and increased concentration of LDL cholesterol. The patients with diabetic also demonstrate that under fasting condition increased level of VLDL, TG and LDL particles were detected, and this malfunction is directly related with endothelial dysfunctions (13). Thus shows that the patient with T2DM, who consume HFD developed number of dysfunction such as endothelial dysfunction, increased FFA, reduced level of antioxidant facility during the fasting period (13). As a result HFD in T2DM patient would develop cardiovascular dysfunction.

Figure: - 5. Shows how oxidative stress causes cardiovascular diseases

Lipid radicals, mitochondrial respiratory chain, NAD (P) H oxidase and xanthine oxidase causes the O2− to increase which react with NO. Thus reduce the production of NO. Reduced level of NO causes endothelial dysfunction by thrombosis, apoptosis, vasoconstriction, oxidative stress and leucocytes adhesion which in turn cause cardiovascular dysfunctions.

Blood pressure

The fetus which exposes to HFD during prenatal and postnatal periods could develops a number of different metabolic syndromes, one of which is hypertension (8). A patient with hypertension means that they have elevated level of blood pressure. Thus increased level of blood pressure could increase the probability of developing coronary heart disease, stroke and many other diseases.

The Khan et al (2004) study evidence that the fetus which consumes HFD during prenatal and postnatal period had more chance of developing hypertension than controlled fetus. To monitor the blood pressure in the offspring they have used radiotelemetry. In the male offspring they have recorded no variation of blood pressure among the controlled and HFD fed dams (Figure 6A). However they have noted that the heart rate of the HFD/HFD fetus was reduced compared to control offspring (Figure 6B). In the female fetus the systolic blood pressure and diastolic blood pressure were increased in the fetus of HFD fed dam compared to control (Figure 7A). Also the fetus fed with HFD/Control diet and fetus fed with Control/HFD diet had elevated blood pressure compared to the control. However no difference of the heart rate was detected among the female fetus which was fed HFD diet and controlled diet (Figure 7B). This increased level of blood pressure in the female offspring of HFD fed dam would eventually causes endothelial dysfunction and as a result cardiovascular dysfunctions occur. This study suggests that high blood pressure in the fetus expose to HFD have gender specific effect.

Figure: - 6. Shows blood pressure (A) and heart rate (B) of male offspring

Image obtained from I.Y. Khan et al (2004): - Figure A shows the monitored diastolic and systolic blood presure of male offspring of HFD/HFD fed dam (shown by the simbole ), HFD/Control fed dam ( ), Control/HFD fed dam ( ), Control/Control fed dam ( ) for a week perod. Figure B shows heart rate in male offspring of HFD/HFD fed dam, HFD/Control fed dam, Control/HFD fed dam , Control/Control fed dam for same week. The results shows that there was no difference of systolic and diastolic blood pressure found amoung the offspring of HFD fed dam and control dam. However the heart rate was reduced in the offspring of HFD fed dams compared to control.

Figure: - 7. shows blood pressure (A) and heart rate (B) of female

Image obtained from I.Y. Khan et al (2004): - Figure A shows the results of monitored systolic and diastolic blood pressure in female offspring of HFD/HFD fed dam (shown by the simbole ), HFD/Control fed dam ( ), Control/HFD fed dam ( ), Control/Control fed dam ( ) for a week perod. Figure B shows heart rate in female offspring of HFD/HFD fed dam, HFD/Control fed dam, Control/HFD fed dam , Control/Control fed dam for same week. As can be seen from diagram the systolic and distolic blood pressure was increased in the offspring of HFD fed dam compared to control, however there was no difference of hert rate found between the groups.

Factors influencing high lipid concentration

Insulin is one of the factors which aid in the lipid metabolism by amending the activity of lipoprotein lipase (LPL), lipolytic enzyme and hepatic lipase (13). LPL is an enzyme which is used for the hydrolysis of TG from the HFD (chylomicron (CM) and very low density lipoprotein (VLDL)) to monoglycerides and free fatty acids (FFA). The FFA and lipoprotein interaction at the endothelium is controlled by LPL (13). The FFA is one of the factors which cause injury to arterial walls. When the LPL bound to the vascular endothelium it reduces VLDL and CM from TG. Thus LPL controls the interaction of FFA or lipoprotein at the interface of the endothelium. Therefore increased intake of fatty acids through HFD increase TG which in turn increase FFA which as a consequence weaken endothelium dependent vasodilatation and onset of coronary dysfunction take place (13).

Endothelial dysfunction also caused by the excess level of FFA which produce prostacyclin and cGMP as consequence oxidative stress increase at the endothelial cell surface (3, 1, 13). This suggests that the oxidative stress have major effect on endothelial function of the fetus of HFD dams. Other factors such as inflammation hypertension, aging, LDL receptor protein activity, hyperlipidemia and reduced physical activities associated with the impaired vascular disease (1, 13).


In the developing fetus the uterus environment is controlled by the prenatal diet and postnatal diet of the mother. Several experimental studies which were carried out in both human and animal evidence that HFD intake of the dam during pregnancy and suckling develops cardiovascular dysfunction in the adult fetus. The maternal HFD causes increase of body weight in the developing fetus which eventually causes cardiovascular dysfunction.

As the predictive adaptive response hypothesis stated if the prenatal diet and the postnatal diet are the same then the fetus would have predict the environment which would causes no effect in the fetus. However if the prenatal and postnatal diets are difference then the fetus prediction of the environment would be different therefore this causes stress in the fetus development and for that reason the fetus develops a number of metabolic disorders such as atherosclerosis, coronary heart disease, stroke, diabetes, hypertension and so on. This suggests that maternal diet during early development of the fetus has influence on the health of the offspring.

The fetus which exposes to low nutrition during early in the development has an abnormal growth patterns which linked to the risk of developing cardiovascular disease (2). The HFD diet of dams during either prenatal or postnatal or in both periods would have harmful effect on the cardiovascular health of the adult fetus. Adult offspring of dams fed with HFD during pregnancy and suckling causes vascular endothelial dysfunction development and also gender linked hypertension which eventually develops cardiovascular dysfunction (8).

This evidenced by the study of P. Ghosh et al (2001) which showed that increased level of SFA during early fetal development determines the vascular dysfunction, irregularities of the aorta fatty acid and plasma lipid irregularity in the adult offspring (1). The fetuses who consume increased level of SFA also develop insulin resistance (1). The elevated level of SFA causes LDL cholesterol in increase. Thus increased level of LDL cholesterol builds in the walls of the arteries and eventually causes atherosclerosis. SFA also increase the production of other lipoprotein such as TG which also have influence of the cardiovascular function. SFA intake during prenatal and postnatal period in the offspring reduces the production PUFA which has negative effects on the health of the heart. Overall the SFA cause endothelial dysfunction and also gives rise to insulin resistance which as a consequence causes activation of inflammatory pathway which in turn raise adiposity, increase blood pressure, reduce baroreceptor reflex, and also reduced endothelial dilation and eventually causes cardiovascular dysfunction. (8)

Maternal low proteins also said to develop cardiovascular dysfunction in the adult offspring as well as HFD (8). In the developing fetus there are three stages such as preimplantation period (the conception time), gestation and suckling period in which sufficient supply of nutrition should be provided in order for the adult offspring to develop healthy cardiovascular system. The HFD during pregnancy and suckling have been suggested to increase circulating lipoprotein particles such as LDL, TG, and reduce HDL than control, which linked to the endothelial dysfunction as a consequence coronary heart disease occurs (1, 8, 9, and 11). As vascular endothelium comes in contact with these harmful atherogenic lipoprotein coronary artery dysfunctions occurs (13). This proves that the offspring exposed to maternal HFD have more chance of developing cardiovascular disease compared to the control offspring.

HFD in the adult offspring reduce vasodilators such as NO and prostacyclin which could cause endothelial dysfunction which progress over time and develop cardiovascular disease. Thus reduce level of NO causes thrombosis, vasoconstriction, apoptosis, and oxidation of lipid and leucocytes adhesion which as a consequence develops cardiovascular disease. Oxidative stress is another factor which causes cardiovascular disease by reducing the production of NO and by increasing the production of LDL cholesterol in the plasma.

Overall the fetus exposed to HFD during gestation and suckling have a harmful effect of the fetal programming because the increased intake of HFD during these critical periods of development give rise to the cardiovascular dysfunctions in the adult offspring.