Restenosis, or re-narrowing of the arterial lumen following vascular interventions to treat atherosclerosis, produces significant mortality and morbidity for thousands of individuals. Transforming growth factor-beta (TGF-2) is an important mediator of restenosis, although the mechanisms that contribute to its effects on the arterial wall remain unclear. In our completed proposal, we explored these mechanisms and hypothesized that inhibition of TGF-2's profibrotic effects and enhancement of its inhibitory effects on smooth muscle cell (SMC) migration and proliferation would provide a venue for controlling intimal hyperplasia. Our studies have provided new insights into the mechanism of action of TGF-2. Contrary to our original hypothesis, TGF-2 produces intimal hyperplasia not through the production of extracellular matrix but rather by stimulating SMC proliferation through the signaling molecule Smad3. Our data also suggest that TGF-2, through Smad3 signaling, may contribute to initmal hyperplasia through the recruitment of bone marrow progenitor cells (BMPC) into the intimal lesion. Lastly we found that TGF-2, through Smad3, appears to produce adaptive remodeling or arterial enlargement, mediated through the protein connective tissue growth factor (CTGF). These novel findings have generated three hypotheses.
In Specific Aim I, we will test the hypothesis that Smad3 levels are elevated in arterial injury and that sustained high levels of Smad3 lead to intimal hyperplasia by converting quiescent SMCs to a phenotype that responds to TGF-2 with proliferation. We will begin by testing the effect of blocking endogenous Smad3 production on neointimal formation in vivo. To better understand the switch of Smad3 activated SMCs from a quiescent to a proliferative phenotype, we will study the relationship between Smad3 and the cyclin-dependent-kinase inhibitor p27. Finally, we will explore whether TGF-2 and Smad3 function in a similar fashion in human restenotic and atherosclerotic plaque.
In Specific Aim II, we will test whether TGF-2, through Smad3, enhances intimal hyperplasia by stimulating arterial SMCs to produce a chemoattractant of BMPCs. In vivo studies, using a rat bone marrow transplant model, have been designed to verify the role in TGF-2 and Smad3 in progenitor cell recruitment. Moreover, we will test the hypothesis that monocyte chemoattractant protein-1 (MCP-1) is the chemoattractant that mediates TGF-2 and Smad3's effect.
In Specific Aim III, we will test whether the TGF-2/Smad3 pathway in SMCs stimulates the production of CTGF, which in turn stimulates adaptive remodeling by differentially regulating synthesis of collagen types I and III. We will show that CTGF is necessary and sufficient for adaptive remodeling and explore the role of collagen type III in this process. With these studies, we expect to gain further insight into TGF-2 and its role in cell proliferation, BMPC recruitment, and arterial remodeling. Ultimately, our findings will lead to the development of therapies that can inhibit intimal hyperplasia and promote adaptive remodeling, providing a solution to the devastating problem of restenosis. Atherosclerosis is the leading cause of death in the United States. Treatments for atherosclerosis are numerous;however, their long term success is impeded by the process of restenosis or re-narrowing of the arterial lumen, which occurs in 30-50% of patients following angioplasty or stenting. The goal of our proposal is to build upon knowledge that we have acquired over the past several years about the molecular mechanisms that underlie TGF-2 and its role in the process of restenosis. The long-term goal is to develop specific therapies that prevent or halt the progression of arterial restenosis, thus reducing morbidity and mortality for thousands of individuals each year.
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|Chen, Guojun; Shi, Xudong; Wang, Bowen et al. (2017) Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats. Biomacromolecules 18:2205-2213|
|Yu, Qing; Shi, Xudong; Greer, Tyler et al. (2016) Evaluation and Application of Dimethylated Amino Acids as Isobaric Tags for Quantitative Proteomics of the TGF-?/Smad3 Signaling Pathway. J Proteome Res 15:3420-31|
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|DiRenzo, Daniel M; Chaudhary, Mirnal A; Shi, Xudong et al. (2016) A crosstalk between TGF-?/Smad3 and Wnt/?-catenin pathways promotes vascular smooth muscle cell proliferation. Cell Signal 28:498-505|
|Chaudhary, Mirnal A; Guo, Lian-Wang; Shi, Xudong et al. (2016) Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery. J Control Release 233:174-80|
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