The establishment and maintenance of a vascular supply are essential for the survival of normal and neoplastic tissues. With the exception of early embryogenesis, new blood vessels are formed from pre-existing vessels by a process called angiogenesis. Angiogenesis occurs during embryonic development, ovarian follicular development and wound healing, and during pathogenesis including solid tumors, diabetic retinopathy and rheumatoid arthritis. The long term goal of my research program is to elucidate biological, molecular and genetic mechanisms underlying regulation of angiogenesis during development and post-natal life. Angiogenesis can be separated into two phases: activation and resolution phases. In activation phase the endothelial cells degrade perivascular matrices, migrate and proliferate, while in resolution phase, endothelial cells cease migration and proliferation. Mechanisms controlling these two distinct phases of angiogenesis remain to be understood. Working hypothesis is that activation-resolution phases are determined by a balance between positive and negative regulators: in activation phase, positive regulators predominate, whereas resolution phase is achieved and maintained by the dominance of negative regulators. While a great deal is known about positive regulators (or angiogenic factors), very little is known about the negative regulators involved in the resolution phase of angiogenesis. With the results from our recent molecular genetic studies about the activin receptor-like kinase-1 (ALK1) deficient mice, we hypothesize that ALK-1 may mediate a negative regulator for the angiogenic balance.
The specific aims of this proposal is to test this hypothesis using in vivo and in vitro approaches. Results from this proposal would enhance our current understanding on the angiogenic balance. This knowledge can be readily applicable to various vascular pathogenesis including atherosclerosis, retinopathy and hereditary hemorrhagic telangiectasia.
|Moon, Eun-Hye; Kim, Yoo Sung; Seo, Jiyoung et al. (2015) Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasia. Cardiovasc Res 105:353-60|
|Tual-Chalot, Simon; Oh, S Paul; Arthur, Helen M (2015) Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. Front Genet 6:25|
|Han, Chul; Choe, Se-Woon; Kim, Yong Hwan et al. (2014) VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 17:823-830|
|Garrido-Martin, Eva M; Nguyen, Ha-Long; Cunningham, Tyler A et al. (2014) Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models--brief report. Arterioscler Thromb Vasc Biol 34:2232-6|
|Tual-Chalot, Simon; Mahmoud, Marwa; Allinson, Kathleen R et al. (2014) Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PLoS One 9:e98646|
|Choi, Eun-Jung; Kim, Yong Hwan; Choe, Se-woon et al. (2013) Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2. PLoS One 8:e63138|
|Chen, Wanqiu; Guo, Yi; Walker, Espen J et al. (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33:305-10|
|Han, Chul; Hong, Kwon-Ho; Kim, Yong Hwan et al. (2013) SMAD1 deficiency in either endothelial or smooth muscle cells can predispose mice to pulmonary hypertension. Hypertension 61:1044-52|
|Nguyen, Ha-Long; Lee, Young Jae; Shin, Jaekyung et al. (2011) TGF-ýý signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development. Lab Invest 91:1554-63|
|Walker, Espen J; Su, Hua; Shen, Fanxia et al. (2011) Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol 69:954-62|
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