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.
Highlights
An urgent medical need has been identified for novel therapies across the spectrum of peripheral arterial disease (PAD) (Gornik 2009), the prevalence of which is rising dramatically with increased occurrence of risk factors including aging, obesity, and hyperglycemia
Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
Microarray analysis of control and collateral mesenteric arteries was performed and the results demonstrate a fundamental difference in the overall collateral gene expression pattern in Spontaneously Hypertensive Rat (SHR) versus normotensive control rats (Wistar Kyoto; WKY)
Summary
An urgent medical need has been identified for novel therapies across the spectrum of peripheral arterial disease (PAD) (Gornik 2009), the prevalence of which is rising dramatically with increased occurrence of risk factors including aging, obesity, and hyperglycemia. These risk factors for PAD promote arterial disease, and suppress the innate capacity for compensation to major arterial occlusion in humans and animal models a 2013 The Authors. The specific mechanisms mediating the impaired growth of collateral arteries in the peripheral circulation remain largely unknown
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