Sex Specific Differences in the Remodeling of a Biopolymer Based Tissue Engineered Vascular Graft

Coronary artery disease is the most widespread form of heart disease and is responsible for over 350,000 deaths per year. CAD is often treated through coronary artery bypass grafting (CABG) with an autologous vessel being used as the bypass graft. However, there are high CABG failure rates due to issues with graft sourcing and graft mechanical properties, with failure rates in post-menopausal (estrogen deficient) women being elevated compared to their pre-menopausal and male counterparts. As a result, the field is working on developing a tissue engineered vascular graft (TEVG) to replace autologous vessels, yet there has been insufficient characterizations of sex and menopausal status as variables in successful TEVG integration. Sex differences in vascular remodeling have been established clinically, with pre-menopausal females having subdued inflammatory responses in atherosclerotic environments and post-menopausal females having insufficient vascular smooth muscle cell (VSMC) remodeling in arteriovenous fistulas. This leads us the believe that VSMC behavior is key in understanding the sex specific differences in vascular grafting outcomes. Our lab has shown that compliance matched TEVGs (CM TEVGs) have an increased number of VSMCs and a more favorable inflammatory response than their stiff counterparts in a small animal model. However, we have noticed that CM TEVGs implanted in female rats show signs of advanced degradation (aneurysm formation, loss or graft materials) when compared to male rats. This suggests that there are sex specific differences in the remodeling of biodegradable TEVGs that may reflect sex specific differences seen clinically. We have also shown that VSMC behavior surrounding our CM TEVGs can be modulated with Transforming Growth Factor Beta 2 (TGFβ2). Low levels of TGFβ2 elution increases VSMC count within the graft. VSMCs live on a phenotypic spectrum that allows them to both modulate blood pressure and contraction during homeostasis and increase migration and ECM remodeling in response to vascular injury. The overarching hypothesis of this work is that the remodeling rate of CM TEVGs is dependent on sex and that this rate is related to the effects of estrogen on VSMC behavior. Aim 1 will assess tissue level differences in mechanics and ECM deposition as well as cellular makeup of CM TEVGs in male and female. Aim 2 will encourage changes VSMC behavior in our CM TEVGs via TGFβ2 to study the effects of estrogen presence on a VSMCs ability to change phenotype in response to vascular injury in ovariectomized (OVX) rats. OVX rats are a widely used post-menopausal small animal model. The successful completion of these aims will elucidate the role of sex on VSMC behaviors that are critical to the successful integration of TEVGs. Project Number: 1F31HL176056-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Katarina Martinet | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10C-B (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17605601A1