Vascular smooth muscle cell fate decisions (i.e. whether a cell differentiates, proliferates, undergoes apoptosis or migrates) play an important role in the pathogenesis of vascular disease including atherosclerosis, intimal hyperplasia and the arterial response to injury. The Hedgehog (Hh) signaling pathway. Notch receptor-ligand interactions and Vascular endothelial growth factor (VEGF) have all been implicated in vascular morphogenesis and modeling of the embryonic vasculature. Hh signaling occurs through the interaction of the Hh protein with its receptor, patched-1 (ptc1) leading to activation ofa transcription factor, Gli, which induces expression of downstream target genes including Ptcl and Gli. The discovery of angiogenic activity for Hh, preferential Ptcl expression in vascular tissue, combined with its mechanosensitivity in vascular cells and known morphogenic functions suggest that Hh might also coordinate vascular cell fate changes in adult tissue. Notch receptor-ligand interactions are also a highly conserved mechanism that regulates intercellular communication and directs individual vascular cell fate during embryogenesis, and more recently in adult cells following injury. The discovery that SHh acts upstream of Notch and VEGF during arterial differentiation combined with Hh regulation of Notch target genes in a variety of cell types, further support a role for Hh-Notch interactions in controlling vascular cell fate. Given these reports in the literature and our preliminary data supporting hemodynamic regulation of both Hh and Notch signaling components in SMC, our central hypothesis is that Hh mediates flow-induced changes in SMC growth (proliferation and apoptosis) and migration via regulation of VEGF/ Notch signaling

Public Health Relevance

Hemodynamic forces, which are associated with blood flow play a fundamental role in maintaining vascular tone, remodeling of blood vessels and associated vascular pathologies. Transduction of these forces can lead to changes in cell growth, death or migration which play an important role in vascular diseases such as atherosclerosis and the arterial response to injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL095650-04
Application #
8309204
Study Section
Special Emphasis Panel (NSS)
Program Officer
Galis, Zorina S
Project Start
2011-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$248,950
Indirect Cost
$87,817
Name
University of Rochester
Department
Surgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Redmond, Eileen M; Liu, Weimin; Hamm, Katie et al. (2014) Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling. PLoS One 9:e84122
Morrow, David; Hatch, Ekaterina; Hamm, Katie et al. (2014) Flk-1/KDR mediates ethanol-stimulated endothelial cell Notch signaling and angiogenic activity. J Vasc Res 51:315-24
Redmond, Eileen M; Hamm, Katie; Cullen, John P et al. (2013) Inhibition of patched-1 prevents injury-induced neointimal hyperplasia. Arterioscler Thromb Vasc Biol 33:1960-4