GENE EXPRESSION IN VASCULAR REMODELING

Project: Research project

Project Details

Description

The biology of the vascular smooth muscle cell (VSMC) is of central
importance in understanding the behavior of the vascular wall in some of
the most prevalent and costly diseases in developed societies, including
hypertension, peripheral vascular disease, and coronary artery disease.
Pathologic VSMC activity is still more evident in the syndromes of
accelerated arteriosclerosis seen after coronary bypass surgery, cardiac
transplantation, and coronary angioplasty. Balloon injury of the rat
carotid artery (RCBI) is an animal model of vascular response to injury
bearing greatest resemblance to the clinical problem of restenosis
following angioplasty. The kinetics of cellular response to denudation and
stretch injury to the carotid artery have been well delineated. Yet
despite intensive investigation, the factors controlling such fundamental
VSMC functions as migration, proliferation, and synthesis and secretion of
proteins comprising extracellular matrix (ECM) remain incompletely
understood. The scientific approach described in this proposal is to apply
a state-of-the-art molecular biologic technique, differential mRNA
display, to an in vivo model system, RCBI, in which these VSMC behaviors
have been well described.

To date, 3 genes with increased expression after RCBI have been confirmed
by Northern analysis; preliminary 3' sequence data do not demonstrate high
homology with any entries in Genbank. Full length cDNAs will be cloned,
sequenced, and examined for sequence similarities to known genes, which
may suggest gene function. Cellular localization within the vessel wall
and tissue expression patterns will be defined. Fusion proteins will be
expressed and evaluated in vitro with migration and proliferation assays
and in Northern analysis of ECM gene expression. Blocking antibodies
raised against fusion proteins will be used in similar studies. Analysis
will then return to the in vivo process by assessing effects of both
fusion protein and blocking antibody on vascular remodeling in the RCBI
model and through the study of transgenic mice. Finally, correlation with
clinical restenosis and atherosclerosis will be evaluated by
immunohistochemistry, in situ hybridization, and quantitative polymerase
chain reaction studies using atherectomy tissue and other specimens of
human vascular pathology. Following the hypothesis that these changes in
cellular activity result from changes in transcription level of particular
mRNA species within the vascular wall, this approach should provide a
unique avenue of insight into the molecular mechanisms determining in vivo
smooth muscle cell behavior during vascular remodeling.
StatusFinished
Effective start/end date1/20/9512/31/95

Funding

  • National Heart, Lung, and Blood Institute

ASJC

  • Cardiology and Cardiovascular Medicine
  • Physiology
  • Cell Biology
  • Histology
  • Developmental Biology

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