Nitric oxide and coronary vascular endothelium adaptations in hypertension

Abstract

This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca(2+) control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex- and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

Keywords: artery; eNOS; estrogen; oxidative stress; polymorphism; sex effect.

Figure 1

Factors affecting NO-mediated endothelium-dependent relaxation of coronary arteries in hypertension. Chemical and hemodynamic forces on the luminal side of the endothelium stimulate eNOS production of NO which can be scavenged by superoxide or diffuse to the vascular smooth muscle cells. At the smooth muscle, available NO activates sGC ultimately affecting Ca²⁺ regulatory proteins, cytosolic [Ca²⁺], and contractile elements, thereby causing arterial relaxation. In hypertension, NO-bioavailability and relaxation of the coronary vascular smooth muscle can be altered due to many factors as discussed in the text and indicated in the Figure by the small arrows. Abbreviations: BK, bradykinin; ACh, acetylcholine; R, receptor; L-Arg, L-Arginine; L-Cit, L-Citrulline; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NO*, nitric oxide; O2*−, superoxide; ONOO⁻, peroxynitrite; VSM, vascular smooth muscle; sGC, soluble guanylate cyclase.

Figure 2

Effects of genetic factors and estrogen on eNOS function and NO bioavailability in coronary arteries with hypertension. Activation of the membrane-bound estrogen receptor can increase eNOS expression and activation as well as reduce the destruction of NO by superoxide, thereby increasing NO available for relaxation. Local hemodynamics, location in the coronary vascular bed, and genetic polymorphisms can also affect eNOS expression and may impact coronary relaxation in hypertension. Abbreviations: R, receptor; ER, estrogen receptor; AT1, type 1 angiotension II receptor; NO, nitric oxide; O2*⁻, superoxide; ONOO⁻, peroxynitrite; MAPK, mitogen-activated protein kinase; Akt, protein kinase B.