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.

Gene Expression and MicroRNA Expression Analysis in Small Arteries of Spontaneously Hypertensive Rats. Evidence for ER Stress

“…Thus, previous studies compared mRNA expression between spontaneously hypertensive rats (SHR) and its normotensive control, the Wistar Kyoto rat (WKY), in kidney [ 2 , 3 ], adrenal gland [ 4 ], vascular smooth muscle cells [ 5 ], and in saphenous arteries[ 6 ]. One study compared collateral resistance arteries from the mesenteric vascular bed of SHR and WKY [ 7 ]. None of these studies included the more recently identified miRNAs, which add another layer of regulation.…”

Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox

“…Taken together, these results suggest that mechanisms other than those related to BMDC function may mediate the impaired compensation observed in the presence of some major vascular risk factors. Such mechanisms may include vascular-specific deficits (42) such as dysfunctional nitric oxide signaling (91) and abnormal redox-dependent regulation of gene expression (82). Appropriate antioxidant therapy might also mediate improvement through altered metabolic status (64); however, it has been shown in insulin resistance that vascular function is impaired by Nox2 independent of altered glucose status (75).…”

The Extraordinary Role of Extracellular RNA in Arteriogenesis, the Growth of Collateral Arteries

“…The role of NFκB signaling in arteriogenesis has not yet been studied in detail; however, this pathway was found to be continuously activated in situations of disturbed blood flow such as in atherosclerosis [18]. Furthermore, an increase in the nuclear translocation of NFκB and hence an increase in the expression of its target genes was observed in a rat mesenteric model of collateral growth [48]. Moreover, NFκB is also able to induce the expression of VEGF [49], suggesting that there might be an interplay between these two avenues of signaling in mediating the effects of eRNA on endothelial activation during arteriogenesis.…”