Determining the Mechanism for Pediatric Vascular Malformations: Investigation of Follicle Stimulating Hormone

Boston Children'S Hospital, Boston MA

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Abstract

Project Summary Abstract The goal of this project is to understand the mechanism by which vascular malformations grow. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific pathways for which targeted therapies can be developed to improve the lives of children affected by vascular malformations and other vascular diseases. Vascular malformations are common, affecting 1/200 children, and cause significant morbidity: disfigurement, obstruction, pain, infection, bleeding, heart failure, and death. Vascular malformations are particularly problematic because they are progressive and enlarge over time. Currently the mechanism for vascular malformations is unknown and there is no cure for these lesions. We propose the novel hypothesis that follicle-stimulating hormone (FSH) may be responsible for the progression of vascular malformations. The secretion of FSH mirrors the life cycle of these lesions (i.e., FSH surges during puberty when a vascular malformation is most likely to expand). Our preliminary data has shown that vascular malformations uniquely express the receptor for FSH (FSHR), in contrast to other normal and pathological vascular tissues. The goal of these studies is to test whether FSH (or its antagonists) affects the growth of vascular malformations. Our first aim will isolate specific cell populations from vascular malformations to identify the cell type(s) that contain FSHR. Our second aim will test the effects of FSH on the angiogenic/vasculogenic properties of human-derived vascular malformation cells. Cell based assays will be used to determine whether FSH causes human vascular malformation endothelial cells, pericytes, or stem cells to exhibit a phenotype that promotes neovascularization. Finally, our third aim will test whether systemically administered FSH (or antagonists) affects the growth of vascular malformations in-vivo. Our validated murine models of lymphatic malformation and venous malformation and newly created in-vivo vascular malformation models will be used for these studies. The effects of FSH on the size, blood flow, and microvessel density on these lesions will be tested. These experiments will be high impact when we succeed in identifying the mechanism responsible for vascular malformations. For the first time we would be able to pursue a targeted approach for treating these lesions. For example, pathway specific topical, intralesional, and/or systemic FSH inhibitors could be developed to prevent the formation or growth of vascular malformations. Also, discoveries into the cause of these lesions will help us understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate neovascularization in other systems (e.g., cancer, tissue repair, engineering).