Leptin Induces Vascular Smooth Muscle Cell Hypertrophy through Angiotensin II- and Endothelin-1-Dependent Mechanisms and Mediates Stretch-Induced Hypertrophy

Abstract

Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated leptin production by greater than 100-fold and leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 Ϯ 1.3 and 30 Ϯ 1% (P Ͻ 0.05), respectively, in the absence or presence of leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ ml). Unstretched RPV weight decreased by 7.5 Ϯ 1.8% in the absence of leptin, whereas in the presence of leptin, weight increased by 6.5 Ϯ 1.8% (P Ͻ 0.05). VSMC size and [ 3 H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of angiotensinogen, the angiotensin type 1 receptor as well as preproendothelin-1, and the endothelin type A receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol-chelating agent methyl-␤-cyclodextrin. Therefore, our study demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

“…40 A further atherosclerotic contribution of leptin is to induce smooth muscle cell hypertrophy and proliferation via endothelin-1-and angiotensin II-dependent mechanisms. 41 Angiotensin II also increases the production of ROS 42 and induces the release of the vasoconstrictor, endothelin-1. 43 Leptin also stimulates the secretion of inflammatory markers such as C-reactive protein 10 and interleukin-6 11 that are directly involved in the development of endothelial dysfunction and atherosclerosis.…”

Leptin and Cardiovascular Disease

“…40 Interestingly, stretching the vascular wall induces expression of both leptin and its receptor in rabbit portal vein. 41 Leptin stimulates synthesis and secretion of endothelin-1 in human umbilical vein endothelial cells 42 and expression of preproendothelin-1 and endothelin ET A receptor genes, angiotensinogen, and angiotensin type 1 receptor expression in rabbit portal vein smooth muscle cells. 41 Finally, leptin stimulates osteoblastic differentiation and hydroxyappatite production by calcifying vascular smooth muscle cells.…”

Inhibition of microRNA-25 by tumor necrosis factor α is critical in the modulation of vascular smooth muscle cell proliferation

“…The vasculature is predominantly comprised of vascular smooth muscle cells (VSMCs), and these cells are involved in the maintenance of vessel tone and blood pressure (1,2). Abnormal proliferation of VSMCs is key in the pathogenesis of cardiovascular diseases, such as coronary heart disease, hypertension and atherosclerosis (3,4).…”