SMAD3 OVEREXPRESSION ENHANCES VASCULAR SMOOTH MUSCLE CELL ATTACHMENT

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Shivam P Patel (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Extracted text; Cardiovascular disease (CVD) is the leading cause of death and illness in the United States and worldwide. Smooth muscle cell (SMC) migration and secretion of extracellular matrix materials are key components of adverse vascular remodeling which is associated with this disease pathology. Cell attachment mediates adherent cell migration and is largely dependent upon integrin binding, matrix metalloprotease balance, and extracellular matrix expression at the leading and lagging edges of migrating cells. Intracellular Smad3 is an important signaling factor that is associated with pro-growth phenotypes and that is involved in a number of vascular growth disorders including atherosclerosis and fibrosis. Because uncontrolled SMC migration and deposition of extracellular matrix are critical components of CVD, the broad purpose of this project is to determine Smad3 as a possible key mediator of growth factor-stimulated vascular fibrosis. Early findings from our lab using the pharmacologic cyclic GMP agonist BAY 41-2272 (BAY) have led us to theorize a promising mechanism through which pathologic vascular SMC growth can be regulated. Preliminary data in rat primary vascular SMCs suggest that BAY not only decreases migration but also decreases total and active Smad3 expression. In light of these findings, in the current proposal my hypothesis is that BAY induces vascular protection in the form of preventing cell migration and by altering matrix balance and that this occurs in a Smad3-dependent fashion. To test this hypothesis, I used two genetic approaches to overexpress or knock-down intracellular Smad3 and then performed cell migration assays and attachment assays in the presence or absence of BAY. Using this approach, we will be able to accurately determine if Smad3 is responsible for our observed BAY-mediated growth protective phenotype. Results displayed that overexpression of Smad3 significantly enhanced vascular SMC attachment after 1 hour and does not appear to impact cell diameter as a function of cell attachment. Early wound healing experiments failed to produce net positive percent recoveries after 10 hours, so further investigation of the role Smad3 plays in BAY41-mediated cell migration protection is necessary. Conclusions from this study will increase our understanding of vascular biology and will also highlight a potential therapeutic target in Smad3 as capable of combating cell migration as a foundation of CVD.

Additional Information

Publication

Thesis

Language: English

Date: 2016

Keywords

vascular smooth muscle, migration, cardiovascular disease, attachment, Smad3, BAY41

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