Intimal hyperplasia is caused by proliferation and migration of intimal smooth muscle cells (SMCs) and contributes to restenosis (the re-occlusion of vessels) after arterial reconstruction. This proposal investigates the possibility that intimal growth occurs because a pathway that normally inhibits excessive proliferation of SMCs after injury is suppressed. We have found that carotid injury in a mouse lacking the type-2 receptor for sphingosine-1-phosphate (S1P2), but not in their wild-type counterpart, results in the formation of a large neointima. Because S1P2-deficient mice develop normally and do not exhibit any vascular phenotype, S1P2 does apparently not play a critical role in the development of the vasculature. Our overall hypothesis is that S1P is generated after injury and binds to S1P2, which causes activation of serum-response factor and its cofactor of the myocardin-like protein family. This transcription factor complex is known to regulate expression of SMC-specific genes, and we hypothesize that these genes inhibit SMC proliferation. This inhibitory pathway is absent in the S1P2 knock-out mouse, and this might be the reason that these animals develop large intimal lesions in response to arterial injury. The goal of this proposal is to test this hypothesis, and four specific aims are proposed.
In aim 1, we will measure expression of SMC- specific genes in injured arteries of wild-type and S1P-deficient mice.
In aim 2, we will define a role for all three S1P receptors expressed in SMCs in the regulation of SRF- dependent genes.
In aim 3, we will characterize the transcriptional complex that is activated by S1P2 and regulates the expression of SMC-specific genes.
In aim 4, we will use micro array technology to identify novel genes in the vessel wall that are directly controlled by S1P2 in response to injury. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088374-05
Application #
8300956
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
2008-08-01
Project End
2013-12-31
Budget Start
2012-07-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$410,850
Indirect Cost
$163,350
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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