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(Circulation Research. 2008;103:289.)
© 2008 American Heart Association, Inc.

Cellular Biology

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

Aaron B. Baker, David S. Ettenson, Michael Jonas, Matthew A. Nugent, Renato V. Iozzo, Elazer R. Edelman

From the Harvard-MIT Division of Health Sciences and Technology (A.B.B., D.S.E., M.J., E.R.E.), Massachusetts Institute of Technology, Cambridge, Mass; the Cardiovascular Division (M.J.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Departments of Biochemistry and Ophthalmology (M.A.N.), Boston University School of Medicine, Mass; the Department of Biomedical Engineering (M.A.N.) Boston University, Mass; and the Department of Pathology, Anatomy, and Cell Biology (R.V.I.), Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Aaron B. Baker, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building E25, Room 442, Cambridge, MA 02139. E-mail abbaker{at}mit.edu

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 β (TGF-β) signaling and intracellular signaling through the ERK pathway. Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between endothelial TGF-β, phosphorylated signaling intermediates, and arterial thickening. Further, studies on ex vivo arteries exposed to varying levels of pressure demonstrated that ERK and TGF-β 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 • hypertension • TGF-β • heparan sulfate proteoglycans • perlecan

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