title: Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat: insight from microarray analysis.
abstract: Analysis of global gene expression in mesenteric control and collateral arteries was used to investigate potential molecules, pathways, and mechanisms responsible for impaired collateral growth in the Spontaneously Hypertensive Rat (SHR). A fundamental difference was observed in overall gene expression pattern in SHR versus Wistar Kyoto (WKY) collaterals; only 6% of genes altered in collaterals were similar between rat strains. Ingenuity® Pathway Analysis (IPA) identified major differences between WKY and SHR in networks and biological functions related to cell growth and proliferation and gene expression. In SHR control arteries, several mechano-sensitive and redox-dependent transcription regulators were downregulated including JUN (-5.2×, P = 0.02), EGR1 (-4.1×, P = 0.01), and NFĸB1 (-1.95×, P = 0.04). Predicted binding sites for NFĸB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFĸB nuclear translocation in collateral arteries of WKY and apocynin-treated SHR, but not in untreated SHR. siRNA for the p65 subunit suppressed collateral growth in WKY, confirming a functional role of NFkB. Canonical pathways identified by IPA in WKY but not SHR included nitric oxide and renin-angiotensin system signaling. The angiotensin type 1 receptor (AGTR1) exhibited upregulation in WKY collaterals, but downregulation in SHR; pharmacological blockade of AGTR1 with losartan prevented collateral luminal expansion in WKY. Together, these results suggest that collateral growth impairment results from an abnormality in a fundamental regulatory mechanism that occurs at a level between signal transduction and gene transcription and implicate redox-dependent modulation of mechano-sensitive transcription factors such as NFĸB as a potential mechanism.
authors.affiliation: Department of Surgery, Indiana University School of Medicine Indianapolis, Indiana, 46202 ; Department of Cellular and Integrative Physiology, Indiana University School of Medicine Indianapolis, Indiana, 46202 ; Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine Indianapolis, Indiana, 46202.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Unthank
authors.forename: Jeanette N
authors.initials: JN
authors.lastname: McClintick
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Labarrere
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Distasi
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Miller
keywords: Arteriogenesis; collateral gene expression; microarray analysis; peripheral vascular disease