Our long-term goal is to ascertain the molecular mechanisms responsible for the normal development and maintenance of the mammalian vasculature and to elucidate molecular lesions underlying vascular pathogenesis. Recent experiments performed on zebrafish have suggested that Notch expression provokes arterial development while its down-regulation results in the default development of veins. Despite these findings in zebrafish, mouse knockout experiments suggest Notch's role in mammilian arterial-venous (AV) development is more complex. Furthermore, the precise cellular and molecular events remain to be defined. To determine the function of the Notch pathway in AV differentiation both in mouse embryos and adults, our lab has developed a mouse model, in which a constituitively active form of Notch is expressed exclusively in endothelial cells. Furthermore, the activated Notch expression is temporally regulatable, thereby allowing us to examine its effects in both developmental and adult vasculature. Using this and other Notch mutants, we will accomplish the following specific aims: define the role of Notch in embryonic AV differentiation (Aim 1); define the role of Notch in adult maintenance of AV identity (Aim 2); define the cellular mechanisms by which Notch specifies differentiation of arteries and veins (Aim 3); and identify the molecular events triggered by Notch in endothelial cells (Aim 4).
The specific aims of this study, engaging morphological, cellular, and molecular analyses, entail both gain-and loss-of-function studies of Notch in endothelial cells. These efforts will reveal the role of Notch in vascular differentiation and maintenance and illuminate potential molecular mechanisms underlying these processes. In the future, this basic understanding of Notch in pre and postnatal mammalian vascular function will guide investigations into its function under pathological conditions, such as ischemic collateral artery formation. Ultimately, our understanding of the Notch pathway may lead to the identification of novel drug targets and therapeutic interventions to vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDD (01))
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Srinivas, Pothur R
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Hwa, Jennifer J; Beckouche, Nathan; Huang, Lawrence et al. (2017) Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow. Sci Rep 7:11965
Nielsen, Corinne M; Huang, Lawrence; Murphy, Patrick A et al. (2016) Mouse Models of Cerebral Arteriovenous Malformation. Stroke 47:293-300
Cuervo, Henar; Nielsen, Corinne M; Simonetto, Douglas A et al. (2016) Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice. Hepatology 64:1302-1316
Murphy, Patrick A; Kim, Tyson N; Huang, Lawrence et al. (2014) Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci U S A 111:18007-12
Lin, Yuankai; Jiang, Weiya; Ng, Jennifer et al. (2014) Endothelial ephrin-B2 is essential for arterial vasodilation in mice. Microcirculation 21:578-86
Nielsen, Corinne M; Cuervo, Henar; Ding, Vivianne W et al. (2014) Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice. Development 141:3782-92
Lindskog, Henrik; Kim, Yung Hae; Jelin, Eric B et al. (2014) Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals. Development 141:1120-8
Kim, Tyson N; Goodwill, Patrick W; Chen, Yeni et al. (2012) Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals. PLoS One 7:e38590
Murphy, Patrick A; Kim, Tyson N; Lu, Gloria et al. (2012) Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med 4:117ra8
Clever, Jared L; Sakai, Yuki; Wang, Rong A et al. (2010) Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration. Am J Physiol Cell Physiol 298:C1087-99

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