Delineating the mechanisms underlying heart valve endothelial repair

PROJECT ABSTRACT Valvular aortic stenosis (VAS) accounts for approximately 3-6% of all congenital heart defects,1 and if left untreated can lead to congestive heart failure in neonates and young infants. Non-invasive, percutaneous balloon valvuloplasty (BVP) is the preferred first step of treatment in pediatrics with the intent to postpone definitive surgery. Outcomes show that while BVP significantly reduces aortic valve (AoV) peak gradient within the first 24 hours in the majority of patients, by the 2-3 year follow up more than half re-stenose and require surgical intervention to repair or replace the dysmorphic and failing valve.2, 3 Therefore, while BVP is favorable in some patients, others are diagnosed with poor clinical outcomes and it is not clear why. Studies report that BVP can injure or even rupture the AoV,4, 5 and studies in rabbits have shown that balloon inflation specifically injures the endothelium.6, 7 Furthermore, our work in mice strongly suggests that direct injury to, or targeted dysfunction of the valve endothelium causes structural deterioration and functional impairment of the AoV, consistent with histological studies in humans reporting poor endothelial integrity in diseased valve tissue.8-11 Taken together, these studies suggest that endothelial damage is a significant contributor of valve pathology, and this may underlie poor outcomes observed in VAS patients following BVP. This raises the question: Can restoring endothelial function be an effective therapeutic strategy to treat structural and functional deterioration of the AoV in susceptible individuals? To explore this, we developed a surgical mouse model of AoV endothelial injury that causes structural and functional deterioration. Using this model, we show that in response to injury, young healthy mice activate a beneficial intrinsic reparative response that leads to endothelial restoration, while this response is impaired in aging mice with known endothelial dysfunction.12 In addition, we propose a mechanism underlying these diverse responses. This proposal will test the overall hypothesis that: The beneficial intrinsic reparative response of the injured valve endothelium requires Tgf1- Cthrc1 signaling between valve endothelial, and underlying valve interstitial cells to promote proliferation and migration of neighboring uninjured cells, leading to endothelial restoration. To test this, we propose three specific aims: 1) Determine the cellular and molecular mechanisms involved in the beneficial intrinsic response following AoV endothelial injury; 2) Determine the requirement of endothelial-Tgf1 for the beneficial intrinsic reparative response of the injured AoV endothelium; and 3) Identify interstitial-Cthrc1 as a critical factor for the beneficial intrinsic reparative response of the injured AoV endothelium. Successful completion will define innovative mechanisms of the intrinsic reparative response as a result of AoV endothelial injury that can be applied to the therapeutic design of mechanistic-based compounds to promote endothelial restoration and prevent structural and functional deterioration, particularly in susceptible individuals.