Autoregulation of blood flow, endothelial nitric oxide synthase and microvascular rarefaction

Microvascular rarefaction associated with hypertension has been noted as a clinical observation for at least 70 years [1]. Rarefaction of arterioles and capillaries occurs in cardiac and skeletal muscle, the intestine, conjunctiva and cutaneous circulation; all tissues possessing significant numbers of reserve vessels unperfused during basal tissue activity. Rarefaction in the gracilis muscle of the spontaneously hypertensive rat begins by closure of arterioles, or functional rarefaction, followed by loss of these vessels resulting in a true structural rarefaction [2]. There are several hypotheses to account for the reduction in number of arterioles and capillaries in hypertensive subjects, including genetic programming, a failure of angiogenesis during maturation, alterations in the renin–angiotensin system and long-term autoregulatory mechanisms. The demonstration of microvascular rarefaction in experimental renal hypertension shows that a genetic predisposition is unnecessary [3] and the return of vessels following restoration of normal blood pressure suggests that angiogenesis is unimpaired [4,5]. Manipulation of dietary sodium shows rarefaction associated with suppression of the renin–angiotensin system, but this occurs independently of changes in blood pressure [6] and is indicative of one of many possible influences on the balance between angiogenesis and apoptosis. The tissues in which rarefaction is observed are noted for the plasticity of their vascularity both to short and chronic demands. An increase in capillary density in skeletal muscle during chronic exercise is well known. Therefore, long-term autoregulation where vascularity is matched to tissue needs appears to remain the best explanation for microvascular rarefaction when arterial pressure is elevated. One mechanism involved in autoregulation of blood flow is release of nitric oxide by endothelial cells in response to elevated shear stress. In addition, nitric oxide synthase may be involved in angiogenesis [7,8]. The bioavailability of nitric oxide is reduced in arteries from hypertensive subjects and it can be hypothesized that this loss would produce functional rarefaction which might lead to structural rarefaction. Along these lines, the study by Kubis et al. appearing in this issue of the Journal of Hypertension [9] is of great interest. Using endothelial nitric oxide synthase (eNOS) knockout mice, they show that arteriolar rarefaction occurs only after the rise in blood pressure whereas antihypertensive treatment with hydralazine prevents the development of rarefaction. Thus, rarefaction is not due to the loss of nitric oxide production per se, but to the elevation of pressure. A corollary to this finding is that rarefaction is an adaptation to hypertension rather than a cause of it. Rarefaction will contribute to elevated peripheral resistance but this can be viewed as another structural adaptation, along with inward, eutrophic remodelling of arterioles, to help autoregulate blood flow and prevent the elevated arterial pressure from entering the capillary bed. Thus, rather than being a cause of hypertension, microvascular rarefaction and arteriolar remodelling should be viewed at the outset as necessary physiological adaptations and only much later do the structural changes become maladaptive, irreversible and lead to target organ damage. The loss of eNOS in the renal vasculature, where it plays a crucial role in tubuloglomerular feedback and regulation of extracellular fluid volume, may be the real cause of hypertension in the eNOS knockout model [10].