: Obstructive vascular diseases (OVD) are the dominant cause of mortality in the developed nations. The dedifferentiation of vascular smooth muscle cells (vsmcs) and their subsequent proliferation and luminal accumulation following vascular injury are pathologic hallmarks of these diseases. In the absence of disease, the mature artery is composed of alternating rings of elastic fibers and vsmcs that surround the endothelium. Elastic fibers are an extensively cross-linked network of the matrix protein elastin. Our previous work demonstrated that mutations in the elastin gene are responsible for a human vascular disease, and loss of elastin is sufficient for inducing an obstructive vascular pathology in mice. We hypothesize that disruption of the elastin matrix is central to the pathogenesis of OVD. We propose three aims.
Aim 1 : We will compare the differentiation, migration and proliferation of vsmcs isolated from mice lacking elastin (Eln -/-) with wild type controls. Our preliminary data indicated that elastin stimulates vsmcs to differentiate into a contractile phenotype, induces their migration and inhibits their proliferation. Using molecular and cell biology techniques, we will describe the signaling pathway and identify the receptor that mediates elastin's regulation of vsmcs.
Aim 2 : We will study elastin's contribution to the mechanical properties of the murine vascular system. We postulate that elastin deposition determines vessel distensibility or stiffness, and these changes have profound affects on pressure and arterial development. Our preliminary data suggests that as the vessel wall becomes stiffer or less distensible there are compensatory increases in arterial pressure and the number of vsmcs rings that develop around an artery.
Aim 3 : We will determine whether restoring the elastin matrix to a site of arterial injury reduces or prevents obstructive vascular disease. To test its therapeutic potential, we have made elastin sheath-stents and begun to determine whether they reduce coronary restenosis in a porcine model. Together with our previous work, the experiments proposed in this grant application seek to demonstrate that elastin matrix injury is a key step in the pathogenesis of obstructive vascular disease and suggest a novel treatment-elastin therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068873-02
Application #
6613808
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2002-08-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$373,750
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99
Larrieu-Lahargue, Frederic; Welm, Alana L; Thomas, Kirk R et al. (2011) Netrin-4 activates endothelial integrin {alpha}6{beta}1. Circ Res 109:770-4
Niebel, Björn; Weiche, Benjamin; Mueller, Alan L et al. (2011) A luminescent oxygen channeling biosensor that measures small GTPase activation. Chem Commun (Camb) 47:7521-3
Smith, Matthew C P; Li, Dean Y; Whitehead, Kevin J (2010) Mechanisms of vascular stability and the relationship to human disease. Curr Opin Hematol 17:237-44
London, Nyall R; Zhu, Weiquan; Bozza, Fernando A et al. (2010) Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med 2:23ra19
Drakos, Stavros G; Kfoury, Abdallah G; Hammond, Elizabeth H et al. (2010) Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart. J Am Coll Cardiol 56:382-91
Chan, Aubrey C; Li, Dean Y; Berg, Michel J et al. (2010) Recent insights into cerebral cavernous malformations: animal models of CCM and the human phenotype. FEBS J 277:1076-83
Li, Dean Y; Whitehead, Kevin J (2010) Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 41:S92-4
Jones, Christopher A; Nishiya, Naoyuki; London, Nyall R et al. (2009) Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat Cell Biol 11:1325-31
Whitehead, Kevin J; Chan, Aubrey C; Navankasattusas, Sutip et al. (2009) The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15:177-84

Showing the most recent 10 out of 12 publications