Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications

Abstract

Endothelium plays a fundamental role in the cardiovascular system, forming an interface between blood and adjacent tissues by regulating the vascular tone through the synthesis of nitric oxide, prostaglandins and other relaxing factors. Endothelial dysfunction is characterized by vasoconstriction, cell proliferation and shifting toward a proinflammatory and prothrombic state. In hypertension endothelial dysfunction may be involved in the initiation and development of vascular inflammation, vascular remodeling, and atherosclerosis and is independently associated with increased cardiovascular risk. Different conditions such as impaired vascular shear stress, inflammation and oxidative stress, activation of the renin angiotensin system have been described as important pathophysiological mechanisms involved in the development of endothelial dysfunction. The release of extracellular vesicles by neighboring cells in the vascular wall has emerged as an important regulator of endothelial function and with potential antihypertensive properties and beneficial effects by counteracting the hypertension mediated organ damage. Furthermore, macrovesicles are emerging as an innovative therapeutic approach for vascular protection, allowing the delivery of bioactive molecules, such as miRNA and drugs interacting with the renin angiotensin system. In this review we summarize the available evidence about the pathophysiological implications of endothelial dysfunction in cardiovascular diseases, focusing on hypertension and its sequelae, and the potential innovative therapeutic strategies targeting the endothelium with the aim to improve vascular function and remodeling.

Keywords: angiotensin II; endothelium; inflammation; reactive oxygen species (ROS); vascular function.

Figure 1

Factor contributing to endothelial function and dysfunction. ACE-2, angiotensin converting enzyme-2; AMPK, AMP-activated protein kinase; Ang, angiotensin; AT1R, type 1 angiotensin II receptor; EGF, epidermal growth factor eNOS, endothelial nitric oxide synthase; EVs, extracellular vesicles; ICAM, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor-1; lncRNA, long-non-coding RNA; LPS, lipopolysaccharide; MCP-1, monocyte chemotactic protein 1; NAPDH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PDGF, platelet derived growth factor; PPAR, peroxisome proliferator receptor; ROS, reactive oxygen species; TGF-β, tumor growth factor-β; TNFα, tumor necrosis factor.

Figure 2

Effects of antihypertensive agents in improving endothelial function. ACE, angiotensin converting enzyme; ACE-i, angiotensin converting enzyme inhibitors; ARBs: angiotensin receptor blockers; AT1R, type 1 angiotensin II receptor; CCBs, calcium channel blockers; CRP, C-reactive protein; eNOS, nitric oxide synthase; G6PD, glucose-6-phosphate dehydrogenase; IL-18, interleukin-18; MCP-1, monocyte chemotactic protein 1; MRA, mineralocorticoid receptor antagonists; NAPDH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species.