Failure of therapeutic vascular interventions, both endovascular and open, is an exceedingly common clinical problem that incurs significant morbidity, mortality and costs. A final common pathway to failure is persistent inflammation leading to proliferation and remodeling of the vessel wall. The resolution of inflammation, formerly considered a passive process, is now understood to be actively governed by specialized pro-resolving lipid mediators (PRMs) derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). While current anti-restenosis agents modulate proliferation primarily via cytotoxic effects, recent work in the Conte Lab has shown that PRMs exert cytostatic effects on vascular smooth muscle cells (VSMC) both in-vitro and in-vivo. In collaboration with the Desai Lab at UCSF, the Conte Lab has also developed a novel biodegradable polymer wrap through which RvD1 can be reliably delivered to the local vascular adventitia. Much has been studied on the various mechanisms through which PRM's modulate inflammation, however relatively little is known about the specific mechanisms through which PRM's modulate cell proliferation. The goal of my project is to characterize the mechanisms through which RvD1 (a docosahexaenoic acid-derived, or D-series, resolvin) exerts cytostatic effects on vascular smooth muscle cells, with specific attention to its effects on the platelet derived growth factor (PDGF) signaling pathway both in vitro and in vivo. This is of great clinical significance as currently available adjuvant pharmacotherapies are limited by their cytotoxicity effects, and endogenous PRMs may provide a novel therapeutic approach to regulate vascular healing.
My first aim i s to determine the effects of RvD1 on injury-related PDGF amplification pathways in rabbit and human VSMC. VSMC proliferation, migration, and leukocyte adhesion will be assessed. PDGF expression will be assessed via RNA, western blot, immunostaining as well as measurements of receptor expression and phosphorylation.
My second aim i s to determine if local adventitial delivery of RVD1 improves post-angioplasty remodeling in a rabbit model, and if the mechanism involves attenuation of PDGF amplification pathways. Using a newly-developed novel biodegradable polymer wrap to administer RvD1 to the artery, I will assess early cellular and molecular events, as well as late remodeling of arteries following angioplasty. Through the opportunities and resources provided by the Conte lab, my personal aim is to develop essential knowledge of and experience with in vitro and in vivo techniques for my future career in translational research and vascular biology. I anticipate that working with Dr. Conte will inspire and invigorate my passion for science and help me maximize my potential as a future productive and innovative surgeon-scientist.
Atherosclerotic vascular disease is a manifestation of chronic inflammation and therapeutic interventions, whether surgical (bypass, endarterectomy) or catheter-based (angioplasty, stenting), commonly fail due to persistent inflammation and proliferation leading to neointimal hyperplasia. Current adjuvant pharmacotherapies are limited by significant cytotoxicity, however novel endogenous pro-resolving lipid mediators derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) exert a cytostatic rather than cytotoxic effect on vascular cells. Better characterization of their molecular mechanisms may lead to the development of new therapies to improve cardiovascular health.
|Wu, Bian; Mottola, Giorgio; Schaller, Melinda et al. (2017) Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications. Mol Aspects Med 58:72-82|
|Lance, Kevin D; Chatterjee, Anuran; Wu, Bian et al. (2017) Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. J Biomed Mater Res A 105:31-41|
|Wu, Bian; Mottola, Giorgio; Chatterjee, Anuran et al. (2017) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury. J Vasc Surg 65:207-217.e3|