Vascular endothelial and smooth muscle cells normally exist in a relatively quiescent growth state. However, both cell types will proliferate in response to vessel wall injury; in addition, abnormal intimal smooth muscle cell (SMC) proliferation is regarded as a key event in the pathogenesis of atherosclerosis. The long-term goal of this proposal is to identify the molecular mechanisms which regulate human vascular cell growth. Since we have recently determined that cultured human SMC will both synthesize and respond to endothelial cell growth factor (ECGF), a member of the acidic-fibroblast growth factor family of polypeptide mitogens, this proposal will focus on the relationship between ECGF and vascular cell proliferation.
The specific aims of this proposal are (i) to analyze ECGF mRNA expression and/or ECGF receptor levels in human primary SMC cultures and in various human SMC strains, during human SMC in vitro phenotypic modulation, and in SMC of unmanipulated and mechanically- injured rat carotid arteries; and (ii) to isolate and characterize cDNA clones representing human SMC genes which are transcriptionally activated in response to ECGF-induced proliferation. Methodology such as RNA gel blotting, RNA in situ hybridization, and ECGF receptor binding assays will be used to address the first specific aim. These studies should clarify the postulated role of ECGF as both a paracrine (endothelial cell) and autocrine (smooth muscle cell) regulator of vascular cell proliferation. The second specific aim, to isolate and characterize cDNA clones representing ECGF-inducible genes, will be achieved by preparing a SMC subtracted cDNA library enriched in proliferative cell-specific clones. This library should prove to be a valuable source of molecular markers for a long- term analysis of SMC growth regulation. Results obtained from the proposed research may aid in the design of specific therapeutic approaches to the problem of SMC hyperplasia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL039727-01
Application #
3471753
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20037