During ischemic disease, endothelial cells lining the blood vessels respond to a variety of stimuli, prompting them to undergo remodeling leading to vascular permeability and angiogenesis. In this Project, we will focus on how integrins, growth factor receptors, tyrosine kinases, and other cell adhesion molecules function in a cooperative manner to influence endothelial cell behavior during ischemic disease. Vascular endothelial growth factor (VEGF) becomes highly expressed during ischemic disease and induces both vascular leak and angiogenesis, processes which require signaling through VEGF Receptor 2 (VEGFR2). We have previously established that VEGF-induced vascular leak requires integrin av|35 and Src family kinases, leading to the disruption of VE-cadherin-mediated cell-cell adhesion. However, the interrelationships and cooperation between these key players,remain poorly understood. In this proposal, we plan to first characterize how integrin ligation influences endothelial cell barrier disruption induced by VEGF during ischemic disease. Next, we will examine how basement membrane proteins exposed during VEGF-induced vascular leak attract and activate platelets, leading to deleterious microthrombi. Lastly, we will determine how semaphorin-SA, thought to influence vascular patterning by suppressing integrin activation, promotes vascular leak in the absence of VEGF, and acts as a negative regulator of VEGF-induced angiogenesis. Together, these studies will serve to provide molecular insight into how integrin signaling mediates the vascular events initated by VEGF. Vascular leak and angiogenesis represent significant vascular remodeling events which have a profound impact on ischemic disease and inflammation. The proposed experiments will provide a better understanding of the signaling pathways in platelets and endothelial cells involved in these complex pathophysiological events, and will serve to identify new therapeutic targets to regulate VEGF-induced vascular leak and vascular remodeling following ischemic injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL057900-16
Application #
8374727
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
16
Fiscal Year
2012
Total Cost
$306,384
Indirect Cost
$108,077
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wilson, RaeAnna; Espinosa-Diez, Cristina; Kanner, Nathan et al. (2016) MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment. Nat Commun 7:13597
Liao, Zhongji; Kato, Hisashi; Pandey, Manjula et al. (2015) Interaction of kindlin-2 with integrin β3 promotes outside-in signaling responses by the αVβ3 vitronectin receptor. Blood 125:1995-2004
Fitzpatrick, Paul; Shattil, Sanford J; Ablooglu, Ararat J (2014) C-terminal COOH of integrin β1 is necessary for β1 association with the kindlin-2 adapter protein. J Biol Chem 289:11183-93
Desgrosellier, Jay S; Lesperance, Jacqueline; Seguin, Laetitia et al. (2014) Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Dev Cell 30:295-308
Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68
Casar, B; Rimann, I; Kato, H et al. (2014) In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated *1 integrin and induction of FAK/PI3K/Akt motility signaling. Oncogene 33:255-68
Ye, Feng; Petrich, Brian G; Anekal, Praju et al. (2013) The mechanism of kindlin-mediated activation of integrin αIIbβ3. Curr Biol 23:2288-95
Cantor, Joseph M; Ginsberg, Mark H (2012) CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci 125:1373-82
Scheppke, Lea; Murphy, Eric A; Zarpellon, Alessandro et al. (2012) Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane. Blood 119:2149-58
Banno, Asoka; Goult, Benjamin T; Lee, HoSup et al. (2012) Subcellular localization of talin is regulated by inter-domain interactions. J Biol Chem 287:13799-812

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