Microvascular responses to cardiovascular risk factors

Abstract

Hypertension, hypercholesterolemia, diabetes, and obesity are among a growing list of conditions that have been designated as major risk factors for cardiovascular disease (CVD). While CVD risk factors are well known to enhance the development of atherosclerotic lesions in large arteries, there is also evidence that the structure and function of microscopic blood vessels can be profoundly altered by these conditions. The diverse responses of the microvasculature to CVD risk factors include oxidative stress, enhanced leukocyte- and platelet-endothelial cell adhesion, impaired endothelial barrier function, altered capillary proliferation, enhanced thrombosis, and vasomotor dysfunction. Emerging evidence indicates that a low-grade systemic inflammatory response that results from risk factor-induced cell activation and cell-cell interactions may underlie the phenotypic changes induced by risk factor exposure. A consequence of the altered microvascular phenotype and systemic inflammatory response is an enhanced vulnerability of tissues to the deleterious effects of secondary oxidative and inflammatory stresses, such as ischemia and reperfusion. Future efforts to develop therapies that prevent the harmful effects of risk factor-induced inflammation should focus on the microcirculation.

Figure 1

Microvascular responses to cardiovascular risk factors.

Figure 2

Oxidant-dependent mechanism underlying the impaired vasomotor function induced by cardiovascular risk factors. AngII = angiotensin II, oxLDL = oxidized low density lipoprotein, AGE = advanced glycosylation end-products, H₂O₂ = hydrogen peroxide, O₂- = superoxide, ROS = reactive oxygen species, NO = nitric oxide, cGMP = cyclic GMP.

Figure 3

Mechanisms implicated in the diminished endothelial barrier function and enhanced leukocyte-endothelial cell adhesion associated with cardiovascular risk factors. Elevated levels of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) result in the phosphorylation and subsequently disassembly of endothelial junctional proteins, which leads to open interendothelial junctions and an enhanced permeation of solutes and transendothelial migration of leukocytes. Transcription-dependent and –independent redox signaling events also promote leukocyte recruitment by increasing the expression of endothelial cell adhesion molecules. Pi, phosphate.

Figure 4

Cardiovascular risk factors induce a prothrombotic phenotype in the vasculature. AngII = angiotensin II, oxLDL = oxidized low density lipoprotein, AGE = advanced glycosylation end-products, ROS = reactive oxygen species, NO = nitric oxide, PGI2 = prostacyclin