Endothelin as a Growth Factor in Vascular Remodeling and Vascular Disease

Abstract

Vascular remodeling is an adaptive process in response to chronic alterations in flow, pressure, and humoral factor(s). This process involves a complex sequence of events, ranging from the sensing and transduction of physical or humoral signals, to the expression of selective genes within the vessel wall, to the process of cellular growth and extracellular matrix production.1 Autocrineparacrine growth factors have been shown to be expressed by vascular endothelial and smooth muscle cells. These substances may play an important role in the remodeling mechanism. A growing body of evidence suggests that the endothelium has the capacity to sense changes in blood flow—shear stress and subsequently to influence vascular smooth muscle contraction by the release of endothelial-derived vasoactive substance(s).2–10 In addition to its role in regulating vascular tone and blood flow, the endothelium may play a role in longterm vascular remodeling related to changes in flow.5 Indeed, the endothelium is capable of producing growth-promoting (e.g., platelet-derived growth factors (PDGF) and basic fibroblast growth factor) and growth-inhibiting (e.g., heparin, prostaglandins, and endothelium-derived relaxing factor) substances.1 The endothelium-derived vasoactive substances can also influence vascular smooth muscle growth. We and others have found that potent vasoconstrictors, such as angiotensin II, induce growth and proliferation of vascular smooth muscle cells.1,11–15 Therefore, when Yanagisawa and colleagues3 isolated the potent peptide vasoconstrictor endothelin from cultured endothelial cells, the question arose as to whether endothelin influenced remodeling of the blood vessel. We describe our investigation of the effect of endothelin on vascular smooth muscle cell growth and examine the potential significance of its mito-genic action in vascular remodeling and disease.