Receptor tyrosine kinase (RTK)-initiated signaling mechanisms are major pathways critical for vascular development and angiogenesis, and mediate signals from angiogenic factors including FGF and VEGF. Our long-term goal is to elucidate the mechanisms by which angiogenic RTK signaling is regulated to direct normal development and homeostasis of the vasculature as a prerequisite to the development of therapeutic interventions of vascular defects and disease. Studies in Drosophila and mammalian cell culture systems have revealed that members of the Sprouty family of polypeptides are negative regulators of FGF signaling as well as other receptor tyrosine kinases (RTKs). During the previous funding period, we demonstrated that Spry2 inhibits FGF signaling at the level of Raf1, thus inhibiting ERK activation. Furthermore, we generated conditional transgenic mice for the tissue-specific expression of Spry1. Targeted expression of Spry1 to the vasculature in early development results in embryonic lethality and a loss of PECAM-positive cells. In addition, we have characterized a new feedback inhibitor of FGF signaling called Sef (similar expression as fgf) and show that Sef is expressed in endothelial cells and induces apoptosis when over expressed. We have shown that Sef physically associates with FGFR1 and inhibits FGFR1 tyrosine phosphorylation and all subsequent signaling downstream of FGFR1. The experiments proposed in this competitive renewal are aimed at elucidating the role of Spry family members in endothelial cell growth and differentiation in vivo. Additional experiments are aimed to determine whether Spry1 functionally interacts with other Spry family members and with Sef to fine tune angiogenic RTK signaling outputs. We hypothesize that Spry is a key regulator of vascular development and homeostasis in vivo, and the output of this regulation is determined by the particular proteins that Spry interacts with in a given cellular context. Therefore we propose the following specific aims: 1) to determine the functional interaction of Spry and Sef as a regulatory network that fine tunes angiogenic RTK- mediated signaling outputs such as ERK activation, 2) to use gain-of-function approaches to determine the role of Spry1 in endothelial cell proliferation and differentiation in transgenic mouse models, and 3) to use loss-of- function approaches to determine the role of Spry1 in endothelial cell proliferation and differentiation in transgenic and knockout mouse models. These studies will provide significant insight into feedback inhibition of RTK signaling via FGF and VEGF in endothelial cells with broad implications for other areas of biology including tumor formation.

Public Health Relevance

Cardiovascular diseases are a major health problem worldwide. Receptor tyrosine kinases (RTKs) play a major role in vascular homeostasis and disease and new pathways are emerging that control the activity of these RTKs. Our goal is to study these pathways at the cellular, molecular and genetic level to increase our knowledge to enable the development new treatments for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065301-06
Application #
7851322
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2000-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$412,466
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
Yang, Xuehui; Gong, Yan; He, Qing et al. (2018) Loss of Spry1 attenuates vascular smooth muscle proliferation by impairing mitogen-mediated changes in cell cycle regulatory circuits. J Cell Biochem 119:3267-3279
Caron, Jennifer M; Ames, Jacquelyn J; Contois, Liangru et al. (2016) Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope. Am J Pathol 186:1649-61
Ames, Jacquelyn J; Contois, Liangru; Caron, Jennifer M et al. (2016) Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway. J Biol Chem 291:2731-50
Contois, Liangru W; Akalu, Abebe; Caron, Jennifer M et al. (2015) Inhibition of tumor-associated ?v?3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18:31-46
Yang, Xuehui; Gong, Yan; Tang, Yuefeng et al. (2013) Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PLoS One 8:e58746
Gong, Yan; Yang, Xuehui; He, Qing et al. (2013) Sprouty4 regulates endothelial cell migration via modulating integrin *3 stability through c-Src. Angiogenesis 16:861-75
Young, Kira; Conley, Barbara; Romero, Diana et al. (2012) BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood 120:4263-73
Contois, Liangru W; Nugent, Desiree P; Caron, Jennifer M et al. (2012) Insulin-like growth factor binding protein-4 differentially inhibits growth factor-induced angiogenesis. J Biol Chem 287:1779-89
Yang, Xuehui; Gong, Yan; Friesel, Robert (2011) Spry1 is expressed in hemangioblasts and negatively regulates primitive hematopoiesis and endothelial cell function. PLoS One 6:e18374
Tang, Yuefeng; Yang, Xuehui; Friesel, Robert E et al. (2011) Mechanisms of TGF-?-induced differentiation in human vascular smooth muscle cells. J Vasc Res 48:485-94

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