Heart valves are essential to maintain unidirectional blood flow, but when compromised as in disease, the structure of the valve is disrupted, resulting in impaired function and progressive heart failure. Unfortunately, there are no effective non-surgical therapeutics to treat valve disease. The aortic valve is composed of three leaflets, each of which consists of two cell types: valve interstitial cells (VICs) and valve endothelial cells (VECs). The VICs produce the extracellular matrix (ECM) which provides the necessary biomechanical properties for function. In addition, a single layer of VECs form a protective barrier around each leaflet and molecularly communicate with underlying VICs to regulate their function. Therefore, it has been hypothesized that disruption of the endothelial barrier allows for dysregulation of the VIC population and subsequent ECM disorganization, leading to biomechanical failure. Despite the importance of this process, little is known about the valve response to endothelial damage.Using a surgical model of endothelial injury, we show that young mice respond to endothelial injury with increased valve cell proliferation, preservation of the VEC barrier and longer-term maintenance of valve structure and function. In aging mice, increased cell proliferation is not observed, and endothelial damage instead leads to increased barrier permeability, leaflet thickening, and valve dysfunction. Therefore, we hypothesize that cell proliferation is critical in the AoV response to endothelial injury and is required for maintaining structural integrity of the AoV and preventing dysfunction. To test this, Aim 1 will determine the fate of proliferating cells in the aortic valve following endothelial injury using the Mosaic mouse model to track clonal populations of proliferating cells. This will be performed in parallel with functional and histological studies. Aim 2 will address the requirement for cell proliferation using a diphtheria toxin mouse model to ablate Ki67-positive cells post-injury. Completion of these aims will provide insight into the process of valve endothelial injury and act as the first step towards development of an alternative valve disease therapeutic.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|