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Mechanisms of Atherogenesis:Role of Shear Stress & Tobacco

Institution: Stanford University
Investigator(s): Gary Gibbons, M.D.
Award Cycle: 1994 (Cycle 3) Grant #: 3KT-0375 Award: $314,974
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards

Initial Award Abstract
Atherosclerosis, a leading cause of tobacco-related mortality, is characterized by the abnormal growth of vascular smooth muscle cells (VSMC). This abnormal proliferation of VSMC is stimulated by well characterized risk factors such as elevations in serum cholesterol, tobacco smoke and hypertension. We are intrigued by the observation that although the entire vasculature is exposed to these risk factors, atherosclerosis is a focal disease that occurs in discrete locations within the vascular tree. Indeed, experimental studies indicate that the proliferation of VSMC and the development of atherosclerosis is inhibited under conditions of increased blood flow or shear stress (the tractive force exerted on the endothelial lining of the, blood vessel by blood flow). The endothelium is ideally situated to regulate this interaction between hemodynamic stimuli and VSMC growth regulation by sensing changes in blood flow and producing growth modulatory mediators. The overall objectives of this project am, 1) to define the molecular mechanisms by which shear stress inhibits VSMC growth and 2) to assess the effect of tobacco constituents on the capacity of the endothelium to modulate VSMC growth in response to flow or shear stress.

In experiments completed to date, we have shown that : 1) conditioned medium derived from endothelial cells exposed to linear shear stress inhibits VSMC growth, 2) this growth inhibitory factor is TGF 1 as defined by a specific bioassay and western blot analysis, 3) the increase in TGF 1 activity in response to shear stress is associated with increased TGF 1 mRNA expression, 4) this increase in TGF 1 mRNA levels is due to increased gene transcription, 5) the induction of TGF 1 gene expression in -response to shear stress is modulated by the activity of a flow-activated potassium channel, and 6) this transcriptional response is mediated by a novel cis-trans interaction in the TGF 1 gene promotor. Additional studies are necessary to further characterize the mechanotransduction system mediating the influence Of mechanical forces on endothelial gene expression regulation. Although we originally postulated that protein kinase C may play an important signal transduction role, blocking this pathway had minimal effects on flow-simulated TGF 1 expression. However, recent studies in our laboratory indicate that tyrosine kinases play an important role in the mechanotransduction apparatus that links hemodynamic stimuli to endothelial cell gene expression regulators. In summary, our studies indicate that flow stimulates a tyrosine-kinase-dependent signaling pathway that increases the activity of transcription factors that activate TGF 1 gene expression via novel cis-trans interactions specific to shear stress.

Overall, we have made substantial progress in the fulfillment of the specific aims of this project. Further characterization of the mechanisms by which hemodynamic stimuli modulate endothelial cell gene expression of growth factors has important implications for our understanding of the causes and prevention of tobacco-related vascular disease.

Mechanisms of vascular remodeling in hypertension: role of autocrine-paracrine vasoactive factors
Periodical: Current Opinions on Nephrology and Hypertension Index Medicus:
Authors: Gibbons GH ART
Yr: 1995 Vol: 4 Nbr: 2 Abs: Pg: 189-196

Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. Modulation by potassium channel blockade
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Ohno M, Cooke JP, Dzau VJ, Gibbons GH ART
Yr: 1995 Vol: 95 Nbr: 3 Abs: Pg: 1363-1369

A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Morishita R, Gibbons GH, Horiuchi M, et al ART
Yr: 1995 Vol: 92 Nbr: 13 Abs: Pg: 5855-5859