Abnormal vascular homeostasis manifests itself in a variety of guises including neointima formation and reduced vascular integrity combined with increased permeability. Neointima growth underlies a number of common diseases including transplant vasculopathy, post- angioplasty and vascular graft restenosis, hypertension, and atherosclerosis among others, while vascular integrity is equally important in a number of systemic and local disorders associated with inflammation and tissue injury. Both of these key facets of vascular pathology tend to be viewed as distinctly different entities that have little in common with each other. Despite decades of investigations, the origin of neointima still remains controversial. Our preliminary data suggest that one potentially important contributor to neointima formation is the Endo-MT process. Endo-MT is thought to result in endothelial cells (EC) trans-differentiating into mesenchymal cell types, including smooth muscle cells (SMC) and fibroblasts. Endo-MT has been implicated in several pathological processes including cardiac fibrosis7 and pulmonary hypertension18, but its very existence is still controversial. It is thought to be driven by TGF? in a SMAD-dependent and independent manner. Furthermore, factors leading to Endo-MT under pathologic conditions or preventing its occurrence in the normal vasculature have not been identified. We propose a novel paradigm stating that impaired endothelial FGF signaling leads to breakdown in vascular homeostasis resulting on one hand in Endo-MT (via decrease in let-7 mediated suppression of TGF? signaling) and on the other in reduced vascular integrity due to the loss of VEGF signaling (decrease in FGF-dependent VEGFR2 expression) and increased permeability (increase VE-cadherin phosphorylation due to reduction in Shp2 expression). Thus impaired EC FGF signaling emerges as the common of denominator of key vascular pathologies. If correct, this hypothesis, and the sequence of events it is outlining, is not only critical to our understanding of the pathophysiology of number most common CV diseases but is equally important for the development of novel therapeutics.

Public Health Relevance

We have identified that FGF signaling plays a critical role in the maintenance of normal blood vessel homeostasis. Loss of this function leads to a number of pathologies underlying some of the most common cardiovascular illnesses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL053793-19A1
Application #
8632650
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Schwartz, Lisa
Project Start
1997-08-01
Project End
2017-12-31
Budget Start
2014-01-06
Budget End
2014-12-31
Support Year
19
Fiscal Year
2014
Total Cost
$438,043
Indirect Cost
$172,438
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Dongying; Simons, Michael (2018) Reprogramming the Endocardium: Trials and Tribulations. Circ Res 122:913-915
Zhang, Feng; Zarkada, Georgia; Han, Jinah et al. (2018) Lacteal junction zippering protects against diet-induced obesity. Science 361:599-603
Yu, Pengchun; Wu, Guosheng; Lee, Heon-Woo et al. (2018) Endothelial Metabolic Control of Lymphangiogenesis. Bioessays 40:e1700245
Kofler, Natalie; Corti, Federico; Rivera-Molina, Felix et al. (2018) The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. J Biol Chem 293:4805-4817
Dejana, Elisabetta; Hirschi, Karen K; Simons, Michael (2017) The molecular basis of endothelial cell plasticity. Nat Commun 8:14361
Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre et al. (2017) FGF-dependent metabolic control of vascular development. Nature 545:224-228
Corti, Federico; Simons, Michael (2017) Modulation of VEGF receptor 2 signaling by protein phosphatases. Pharmacol Res 115:107-123
Chen, Pei-Yu; Qin, Lingfeng; Li, Guangxin et al. (2016) Fibroblast growth factor (FGF) signaling regulates transforming growth factor beta (TGF?)-dependent smooth muscle cell phenotype modulation. Sci Rep 6:33407
Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2
Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-? and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7

Showing the most recent 10 out of 118 publications