Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway

Abstract

Abstract-Mechanical forces are potent modulators of the growth and hypertrophy of vascular cells. We examined the molecular mechanisms through which mechanical force and hypertension modulate endothelial cell regulation of vascular homeostasis. Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells. Mechanical strain stimulated the production of perlecan and heparan sulfate glycosaminoglycans by endothelial cells. By inhibiting the expression of perlecan with an antisense vector we demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control. Mechanical regulation of perlecan expression in endothelial cells was governed by a mechanotransduction pathway requiring autocrine transforming growth factor ␤ (TGF-␤) signaling and intracellular signaling through the ERK pathway.Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between endothelial TGF-␤, phosphorylated signaling intermediates, and arterial thickening. Further, studies on ex vivo arteries exposed to varying levels of pressure demonstrated that ERK and TGF-␤ signaling were required for pressure-induced upregulation of endothelial HSPG. Our findings suggest a novel feedback control mechanism in which net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from VSMCs and growth inhibitory signals from endothelial cells. Key Words: mechanical strain Ⅲ hypertension Ⅲ TGF-␤ Ⅲ heparan sulfate proteoglycans Ⅲ perlecan T he endothelium is a dynamic constituent of the vascular system that exerts remarkable control over diverse process such as hemostasis, inflammation, and the regulation of vascular tone. 1,2 In addition to interacting with blood constituents and circulating cells, the vascular endothelium is exposed to a distinct mechanical environment consisting of hemodynamic shear stress and mechanical stretch from blood pressure. As a result, endothelial cells are optimally situated as both sensors and effectors in the vascular remodeling process. An extensive body of scientific work supports the concept that vascular cells respond to their mechanical environment. 3,4 In vitro, shear stress and stretch stimuli regulate endothelial cell production of regulatory molecules including nitric oxide, 5 reactive oxygen species, 6 inflammatory cell adhesion molecules, 7 and extracellular matrix molecules. 8 Similarly, vascular smooth muscle cells (VSMCs) respond to mechanical stimuli by altering their expression of cell adhesion and extracellular matrix molecules 9 as well as increasing proliferation and migration. 10,11 An essential function of the intact endothelium is the paracrine regulation of the growth and phenotype of underlying VSMCs. Soluble heparan sulfate proteoglycans (HSPGs) are intimately involved in endothelial inhibition of VSMC proliferation. 12-14 These complex molecules are composed of a core protein covalently coup...

PDGF-BB and TGF-β1 on cross-talk between endothelial and smooth muscle cells in vascular remodeling induced by low shear stress

“…PDGF-BB and TGF-β1, which are known to be involved in cellular communication and function modulation (17)(18)(19), and three other related molecules, lamin A, LOX and ERK1/2, were selected for further studies.…”

Pressure Activates Src-Dependent FAK-Akt and ERK1/2 Signaling Pathways in Rat Hepatic Stellate Cells

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Loss of Syndecan-1 Induces a Pro-inflammatory Phenotype in Endothelial Cells with a Dysregulated Response to Atheroprotective Flow

“…For Western blotting, a 1:500 dilution of primary antibodies (phospho-Akt (Ser 473 ) and Akt from Cell Signaling) was used for overnight incubation at 4°C, and a 1:3500 dilution of secondary antibodies (Santa Cruz Biotechnology) was used at room temperature for 2 h as previously described (25).…”