During normal development, vascular smooth muscle cells (VSMC) undergo differentiation from a proliferative phenotype characteristic of neonatal and embryonic vessels, to a contractile phenotype associated with adult vessels. In contrast to development of cardiac or skeletal muscle, VSMC retain much greater plasticity. In adult VSMC, phenotypic modulation resulting in changes in altered expression of a number of muscle-specific genes (SM-markers), results in cells with altered contractile, proliferative and migratory capacity. Transcriptional control of these genes occurs in response to multiple extracellular stimuli including circulating factors, extracellular matrix and mechanical forces. We hypothesize that phenotypic modulation requires sensing by VSMC of these multiple inputs, which integrate at the level of common signal transduction pathways. These pathways act on transcription factors, most critically serum response factor (SRF), that bind to the promoter elements of multple target genes. The goal of this proposal is to define these molecular signaling events and determine how they regulate transcription. During the previous funding period we have demonstrated that coordinated induction of SM-markers by arginine vasopression (AVP) is mediated through activation of the JNK and p38 family of MAP kinases. Induction by mechanical forces also involves these pathways. Conversely, PDGF suppression of SM-gene expression is mediated through activation of Ras and the PI3 kinase/Akt pathways. We have also demonstrated that growth of VSMC on matrices of different composition, through engagement of specific integrins and modulation of cytoskeleton, results in changes in expression of SM-markers. SRF is critical for regulation in all of these settings, and shows altered phosphorylation and subcellular localization. In this application we will focus on understanding the integration of signals generated by vasoconstrictors such as AVP, growth factors, and cell attachment resulting in alterations in gene expression.
Three specific aims are proposed.
Specific aim 1 will examine the role of MAP kinase and Rho family members in mediating the inductive effects of AVP. The second specific aim will define the mechanisms whereby Ras and Akt cooperate to mediate regulation of SM-gene expression by PDGF and redistribution of SRF. The final specific aim will examine the role of SRF phosphorylation in mediating control of SM-gene expression. These studies should provide a detailed molecular understanding of the events that control phenotypic remodeling in VSMC, and provide potential new targets for controlling this process in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK019928-30
Application #
7667919
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
30
Fiscal Year
2008
Total Cost
$389,533
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Li, Chunling; Wang, Weidong; Rivard, Christopher J et al. (2011) Molecular mechanisms of angiotensin II stimulation on aquaporin-2 expression and trafficking. Am J Physiol Renal Physiol 300:F1255-61
Wang, Weidong; Li, Chunling; Summer, Sandra et al. (2010) Interaction between vasopressin and angiotensin II in vivo and in vitro: effect on aquaporins and urine concentration. Am J Physiol Renal Physiol 299:F577-84
Schrier, Robert W (2010) Systemic arterial vasodilation, vasopressin, and vasopressinase in pregnancy. J Am Soc Nephrol 21:570-2
Andres-Hernando, Ana; Lanaspa, Miguel A; Li, Nanxing et al. (2010) Effects of 2-bromoethanamine on TonEBP expression and its possible role in induction of renal papillary necrosis in mice. Toxicol Sci 118:510-20
Furgeson, Seth B; Simpson, Peter A; Park, Insun et al. (2010) Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation. Cardiovasc Res 86:274-82
Lanaspa, Miguel A; Andres-Hernando, Ana; Rivard, Christopher J et al. (2009) ZAC1 is up-regulated by hypertonicity and decreases sorbitol dehydrogenase expression, allowing accumulation of sorbitol in kidney cells. J Biol Chem 284:19974-81
Schrier, Robert W (2009) Interactions between angiotensin II and arginine vasopressin in water homeostasis. Kidney Int 76:137-9
Berl, Tomas (2009) How do kidney cells adapt to survive in hypertonic inner medulla? Trans Am Clin Climatol Assoc 120:389-401
Bansal, Shweta; Lindenfeld, JoAnn; Schrier, Robert W (2009) Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist? Circ Heart Fail 2:370-6
Schrier, Robert W; Masoumi, Amirali; Elhassan, Elwaleed (2009) Role of vasopressin and vasopressin receptor antagonists in type I cardiorenal syndrome. Blood Purif 27:28-32

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