Vascular homeostasis is the process of balancing the level of contraction and relaxation of the endothelium within certain limits.Dod et al., 2010 The control of vascular tone is achieved through various compounds which control this vasoconstriction or vasodilation of the endothelium.(Maiorana et al., 2003) Endothelial dysfunction is a condition which causes vasoconstriction of the vasculature and is the major underlying cause of atherosclerosis. Exercise plays a major role in the protection of the endothelium and has been shown to have a positive effect on the endothelium and reduce the incidence of cardiovascular morbidity.(Dod et al., 2010) Exercise leads to increased pressure on the walls of major arteries. Due to this increased cardiac output and pressure there are vasodilatory mechanisms in place to ensure that peripheral resistance is reduced in order to maintain the wall shear rate of the blood.(Ferguson et al., 2000) Nitric oxide is released in response to these stimuli of increased blood flow rate and wall shear rate.(Hambrecht et al., 1998)
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NO release is therefore a key vasodilatory mechanism and is vital in reducing the extent of endothelial dysfunction. NO has many effects which contribute to a healthy endothelium such as reduction of cellular adhesion and migration which reduce the chance of developing conditions such as atherosclerosis.(Higashi and Yoshizumi, 2004)
Morphological changes to endothelium
The endothelium is also thought to change morphologically in response to the shear stress caused as a consequence of the increased oxygen demand of the muscles during exercise. Chemical and mechanical mechanisms become active when intensive exercise is undertaken, these prepare the vasculature for future stress on the endothelium.(Laughlin, 2008) The lumen of capillaries is thought to become larger after exercise and studies have also shown that myocardial capillaries in the heart become thinner. This thinning of the myocardial capillaries may encourage transport of ions to the tunica media of the endothelium. (Marsh and Coombes, 2005) This transport of ions to the tunica media may help to maintain the endothelium in a stable state and reduce the extent of endothelial degeneration. In a study on rats the thickness of the basement membrane of the endothelium was considerably reduced after just one session of intensive exercise, 6 hours after the exercise the basement membrane was shown to have reverted back to normal. This goes to show that immediate shear stress can have instant effects on the morphology of the endothelium.(Marsh and Coombes, 2005) It could therefore be suggested that exercise is likely to reduce endothelial dysfunction through structural changes as well as through chemical mediators.
Upregulation of NO production
An immediate increase in exercise levels increases the amount of NO released however interestingly, increasing daily levels of exercise also increases the basal levels of NO released from the endothelium. This basal upregulation of NO released from the endothelium is thought to stay for weeks after the bout of regular exercise. This chronic upregulation of the endothelium is not only limited to the muscle in question but can be a systemic process aiding the vasculature all around the body to upregulate NO production.(Ferguson et al., 2000) Although exercise is a very effective way of improving the health of the endothelium it has been shown that there is much more marked improvement in individuals already suffering from endothelial dysfunction rather than healthy individuals. This is not to say that exercise is not beneficial for people with a healthy endothelium. However as scientific literature on the effects of NO on the endothelium usually uses test subjects with abnormal or unhealthy endothelium's the data must be interpreted with care.(Maiorana et al., 2003) NO is synthesised by an enzyme known as NO synthase. NOS synthase exists in three different forms and each form is identified based on the location it was originally found. Endothelial NOS is referred to as eNOS. This form of nitric NOS is calcium sensitive and is constitutively expressed in the endothelium of many parts of the cardiovascular system. nNOS refers to the neuronal isoform of NOS and is also calcium dependant and present in many parts of the cardiovascular system. The third type of NOS differs from the other two types as it is not constitutively expressed in the endothelium. Instead it is "inducible", this means that it can be induced by chemical mediators. It is therefore called iNOS, it is not calcium sensitive and must be induced by signalling molecules such as cytokines and TNF. (Noble A., 2009)
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Exercise has been shown to affect the expression at a genetic level of precursors from which these different NOS enzymes are formed. Increased mRNA precursors of eNOS and iNOS were isolated from wistar rats after the animals had undergone 10 weeks of regular exercise.(Yang, 2001) This shows that regular exercise upregulates the expression of NOS isoforms leading to an upregulation of the basal expression of NO. Exercise therefore clearly impacts hugely on NO induced vasodilation. This NO release can then combat endothelial dysfunction by reducing hypertension and cellular adhesion. However exercise is not the sole factor regulating NO synthesis. NOS enzymes can also be affected by neurotransmitters such as bradykinin and further research into ACE inhibitors as a way of inducing NO production may yield promising results. (Rajagopalan and Harrison, 1996)
Figure 1: Shows pathway and enzymes NO activates in order to cause vasodilation of the endothelium
NO vasodilation mechanism
Once NOS has been activated and NO has been produced, a complex chain of events occurs mediating an eventual vasodilation of the vasculature. (figure1) An enzyme known as guanylate cyclase is the first port of call for NO. NO binds to the haem part of the GC enzyme. For this reason the GC enzyme is thought of as a NO sensor molecule.(Poulos, 2006) NO binding causes an upregulation in GTP cyclase activity. This catalyses the conversion of GTP to cGMP. This increase in cGMP then activates the intracellular signalling molecule "protein kinase A". The mechanisms by which protein kinase A regulates endothelial vasodilation are poorly understood. There are several mechanisms that have been hypothesised by which protein kinase A can actively decrease the amount of intracellular calcium ions in the smooth muscle of the endothelium. As calcium ions control the contractile activity of the smooth muscle, this would explain how NO acts as a vasodilator. Protein kinase A may phosphorylate a protein known as phospholamban.(figure 1) Phospholamban regulates the calcium pump within cells of the endothelium, this calcium pump known as SERCA re-sequesters calcium back into the sarcoplasmic reticulum.(Karczewski et al., 1998) Phospholamban inhibits this pump under normal circumstances. However when phospholamban is phosphorylated by protein kinase A this inhibition is removed. In an experiment involving inhibition of the saroplasmic reticulum ATPase (SERCA), the normal vasodilatory effects of NO were abolished pointing strongly to the involvement of this enzyme.(Cohen et al., 1999) NO mediated phosphorylation of phospholamban is therefore thought to operate by promoting the sequestration of calcium ions into intracellular stores via the SERCA enzyme. This reduces the amount of free calcium available to the smooth muscle cells and therefore causes vasodilation.(Cohen et al., 1999)
Other vasodilators (prostacyclin)
NO is one of the most important mediators of vasodilation however the other vasodilatory compounds should not be forgotten, prostacyclin is a good example of another vasoactive compound. As well as NOS the endothelium also expresses COX-1 which is necessary for the production of prostacyclin (PGI2).(Mitchell et al., 2008) COX-1 synthesises prostaglandin H2 which is converted to PGI2 by the prostaglandin H synthase enzyme. Exercise has been shown to elevate PGI2 levels considerably, this opposes vasoconstriction of the endothelium and also suppresses platelet activity.(Petidis et al., 2008) Endothelial dysfunction is characterized by a decrease in NO and PGI2 levels, if exercise can increase the levels of both of these compounds this indicates large benefits for the endothelium.
Until now almost all discussion has been on the beneficial effects of exercise on the endothelium. However intensive exercise also increases the amount of "oxidative stress" on the body. Free radical O2- and H2O2 are created as by-products when oxidative phosphorylation occurs in the mitochondria. As exercise requires large amounts of ATP the amount of by-products produced is increased.(Rang, 2007) The body has a natural way of dealing with these free radical species by using enzymes, superoxide dismutase and glutathione peroxidise are examples of these.(figure 2) O2- is dismutated to H2O2 by superoxide dismutase, H2O2 is then converted into H2O in most cases via the catalase or glutathione peroxidise enzymes. H2O2 is also reduced to OH- in the fenton reaction. The term "oxidative stress" refers to an increase in the number of reactive oxygen species compared to the level of antioxidant molecules.(Urso and Clarkson, 2003) As well as increasing the need for oxidative phosphorylation exercise can also increase the number of free radicals in other ways. Macrophages repair damaged tissue and in the process release O2- free radicals, also prostanoid metabolism can lead to increased free radical production.(Rattan, 2001) The endothelium is very sensitive to increased oxidative stress and free radical production is a major cause of endothelial dysfunction and cardiovascular disease. (Wadsworth, 2008) The levels of free radical species produced by increasing exercise are different with each individual and it is impossible to conclude that free radical production due to intensive exercise is related to endothelial dysfunction. Also as discussed previously the body has antioxidant mechanisms that neutralize the free radical species, the threshold of reactive oxygen species needed to cause damage may be different with each individual.(Urso and Clarkson, 2003) Athletes are increasingly taking antioxidants as supplements to counteract oxidative stress however there is no conclusive evidence to suggest that these are necessary. Trained athletes have additionally been found to have an increased resistance to oxidative stress. In a study on men who performed regular vigorous exercise it was demonstrated that blood levels of reactive oxygen species was very low compared to control groups.(Bloomer et al., 2007) There has been recent evidence that suggests that a certain small level of oxidative stress is also necessary for exercise to mediate its beneficial effects to muscles and the endothelium. The reactive oxygen species may provide signalling mechanism which mediate adaptation of tissues. Overall, no conclusions can be made as to whether antioxidants should be taken when exercising or whether exercise even elevates reactive oxygen species to a level that is harmful. Perhaps the best course of action is regular exercise coupled with a diet rich in antioxidants.(Urso and Clarkson, 2003)
Figure 2: Enzymatic antioxidant pathways which deal with ROS (reactive oxygen species)
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In conclusion exercise has numerous beneficial effects on the endothelium. The most important is arguably increased NO production, this provides a vasodilatory effect on the smooth muscle of the vasculature which is indispensible for prevention of atherosclerosis. Additionally to this prostacyclin opposes vasoconstriction reducing the pathogenesis of conditions such as endothelial dysfunction. Both NO and prostacyclin reduce cellular adhesion reducing the formation of atherosclerotic plaques. Not all effects of exercise where found to be beneficial, reactive oxygen species production increases with intensive exercise. These may have a damaging effect on cells of the endothelium and therefore may actually increase the extent of endothelial dysfunction. However the evidence to suggest that exercise has damaging effects on the endothelial is sparse, reactive oxygen species have not been proven to attain threshold damaging levels during exercise. In the light of this information the advantages of exercise seem to outweigh the disadvantages. Whether exercise can be supplemented with antioxidants in the future is however also yet to be proven.