instmctions): (Project 5, Apte) Versican Proteolysis and Regulation of Vascular Smooth Muscle Function -Versican, an extracellular matrix (ECM) proteoglycan, is a prominent product of vascular smooth muscle cells (VSMCs) and the developing heart. Its proteolytic turnover by ADAMTS metalloproteases is a major mechanism underlying cardiac outflow tract and myocardial development. In contrast, the role of ADAMTS-mediated versican proteolysis in the vascular wall is poorly understood. Our preliminary data demonstrate that ADAMTSI, ADAMTS5 and ADAMTS9 are expressed by embryonic and adult VSMCs, and we propose a cooperative mode of action of these proteases in versican turnover. Preliminary studies identified aortic wall anomalies associated with versican accumulation in Adamts9+/- mice . We found that ADAMTS proteolytic activity influenced the volume of the hyaluronan-based pericellular matrix of cultured fibroblasts, of which versican is a critical component. Associated with this change, we saw enhanced TGF-beta signaling and acquisition of a myofibroblastic phenotype. The hypothesis underlying the proposal is that ADAMTS proteases work cooperatively in VSMCs to regulate the structural and pericellular matrix. Through this physiological function, they are proposed to influence VSMC behavior and the development and integrity of the vasculature. The hypothesis will be addressed by taking a combined genetic and cell biology approach. Using mice deficient In Adamtsi, Adamts5, and Adamts9, we will use combinatorial genetics in aim 1 to define the individual and cooperative roles of these genes in the vasculature. Using VSMCs isolated from these mouse mutants, we will determine the role of ADAMTS proteases in influencing VSMC function in aim 2. We will complement genetic experiments with approaches that use wild-type VSMCs in conjunction with chemical ADAMTS inhibition, as well as gain-of-function strategies (increased expression of versican and ADAMTS) to comprehensively define the underlying mechanisms. Since versican in the pericellular matrix is complexed to hyaluronan (HA), we will undertake quantitative analysis of the effect of ADAMTS proteases on the dynamics of the versican-HA glycocalyx using resources available in Core B.
These experiments address a critical area of vascular biology and medicine, with potential relevance for developmental defects, aneurysms, re-stenosis and atherosclerosis. The research is expected to provide new candidate genes for genetic predisposition to these conditions, and the mechanisms that are uncovered are likely to offer potentially new therapeutic approaches.
|Alkhouri, N; Eng, K; Cikach, F et al. (2015) Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls. Pediatr Obes 10:23-9|
|Dababneh, Luma; Cikach, Frank; Alkukhun, Laith et al. (2014) Sublingual microcirculation in pulmonary arterial hypertension. Ann Am Thorac Soc 11:504-12|
|Foulcer, Simon J; Nelson, Courtney M; Quintero, Maritza V et al. (2014) Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5. J Biol Chem 289:27859-73|
|Dubail, Johanne; Aramaki-Hattori, Noriko; Bader, Hannah L et al. (2014) A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis 52:702-12|
|Aytekin, Metin; Tonelli, Adriano R; Farver, Carol F et al. (2014) Leptin deficiency recapitulates the histological features of pulmonary arterial hypertension in mice. Int J Clin Exp Pathol 7:1935-46|
|Coulson-Thomas, Vivien Jane; Gesteira, Tarsis Ferreira; Hascall, Vincent et al. (2014) Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx. J Biol Chem 289:23465-81|
|Ghatak, Shibnath; Bogatkevich, Galina S; Atnelishvili, Ilia et al. (2014) Overexpression of c-Met and CD44v6 receptors contributes to autocrine TGF-?1 signaling in interstitial lung disease. J Biol Chem 289:7856-72|
|Navaneethan, Sankar D; Wehbe, Edgard; Heresi, Gustavo A et al. (2014) Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 9:855-63|
|Xu, Weiling; Janocha, Allison J; Leahy, Rachel A et al. (2014) A novel method for pulmonary research: assessment of bioenergetic function at the air-liquid interface. Redox Biol 2:513-9|
|Ghatak, Shibnath; Misra, Suniti; Norris, Russell A et al. (2014) Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis. J Biol Chem 289:8545-61|
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