DESCRIPTION (provided by applicant): The maintenance of endothelial functions is essential for vascular homeostasis, vascular development, angiogenesis and vasomotor tone. The dysregulation of the vascular endothelium in response to vascular injury and stress contributes to many cardiovascular diseases such as inflammation, atherosclerosis, peripheral vascular disease and cancer. The peroxisome proliferator-activated receptors (PPARs) family, important regulators of glucose and fatty acid metabolism, is one important signaling pathway involved in regulating pathophysiologic functions such as angiogenesis, inflammation and atherosclerosis. The PPAR family consists of three ligand-activated receptors: PPARα, PPARß/δ and PPARγ, all of which are expressed in endothelial cells. Although the importance of PPAR signaling in the endothelium is now recognized, an accurate understanding of the mechanisms responsible for their pathophysiologic regulation remains largely unknown. Recently I identified LRP1 (low density lipoprotein receptor-related protein 1) as a novel regulator of PPAR signaling. LRP1 is a heterodimer composed of a 515-kDa α chain (LRP1α) possessing four extracellular ligand binding domains and an 85-kDa membrane-anchored intracellular ß chain known for transducing signals. LRP1 is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium is almost unknown. Our recent preliminary data demonstrate that LRP1ß interacts with PPARß/δ in the nucleus and regulates its transcriptional activity, suggesting that LRP1 acts as a novel regulator of PPARs in endothelial cells. In addition, we observed that LRP1 is induced by hypoxia and is a novel regulator of Bmp signaling pathway through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator), which itself plays an essential role in the regulatin of endothelial functions such as angiogenesis and atherosclerosis. Moreover, we observe that LRP1 regulates endothelial growth, migration, inflammation and tubulogenesis in vitro, zebrafish vascular development and mouse retinal angiogenesis in vivo. These observations lead us to hypothesize that LRP1 acts as an essential regulator of endothelial function through its integration of signaling responses to a diverse range of stimuli to activate downstream effectors such as PPARs. The aims include (1) investigate the role of LRP1 in the regulation of endothelial signaling events; (2) elucidate the effects of LRP1 on endothelial cellular events; (3) study the effects of LRP1 deficiency on angiogenesis and atherosclerosis in vivo. The knowledge gained from this proposal will provide novel therapeutic targets and strategies for treating angiogenesis-dependent diseases and atherosclerosis.

PUBLIC HEALTH RELEVANCE: The vascular endothelium plays an essential role in both health and the development of many cardiovascular and circulatory diseases. We use LRP1 signaling axis as an important model system to elucidate signaling pathways and cellular events in the pathophysiologic regulation of endothelial function, and suggest new and unexpected therapeutic targets and strategies against blood vessel ischemic disease, inflammation, atherosclerosis and other related diseases.