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Abstract

Studying the myocardial microvasculature has been challenging, in part, due to technical imaging limitations in vivo and limited physiologically relevant in vitro models. This thesis reports the development of two on-chip models of human microvasculature to study the impact of the tissue microenvironment on cardiac vascular remodeling—with a specific focus on the contributions of stromal cells, cardiomyocytes, and female sex hormones in regulating microvascular behavior. First, the effect of vascular-stromal crosstalk was studied by assessing the impact of tissue-specific co- cultured fibroblasts on microvascular development. The results presented herein, demonstrate that fibroblasts impact microvascular morphology by increasing branch density while decreasing vessel diameter. Cardiac fibroblasts, unlike lung fibroblasts, cause a reduction in vascular barrier function. Moreover, lung and cardiac fibroblasts had a differential response to TGFβ1, mimicking different aspects of fibrosis on-chip. This published first work highlighted the importance of fibroblasts in developing tissue-specific models for vascular research. Next, a 3D model that mimics coronary microvascular structure and barrier function was developed to explore vascular-myocyte crosstalk. Human-induced pluripotent stem cell (hiPSC)-derived cardiac spheroids (CS) were co-cultured with cardiac microvasculature to assess the impact of myocyte crosstalk on microvessel development. Cardiomyocytes altered vessel morphology and improved barrier function in a spatially dependent manner. This vascularized cardiac model was used to investigate the cardioprotective roles of the sex hormones estrogen (E2) and progesterone (P4) under inflammatory conditions. Pre-treatment with these hormones preserves endothelial barrier integrity during TNFα-induced inflammation, potentially by modulating endothelin-1 secretion. Overall, these models highlight the critical role of cellular crosstalk and the tissue microenvironment in vascular development and showcase their utility in modeling vascular perturbations.