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Potential Molecular Basis for Impaired Collateral Artery Growth in the Spontaneously Hypertensive Rat

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 the overall gene expression pattern in SHR vs. Wistar Kyoto (WKY) collaterals (only 6% of the genes altered in collaterals were similar). IPA analysis identified major differences between WKY and SHR in networks and biological functions related to cell growth and proliferation and gene expression. Canonical pathways identified by IPA in WKY but not SHR included nitric oxide and renin angiotensin system signaling. The angiotensin type 1 receptor (AT1R) exhibited up-regulation in WKY collaterals, but down-regulation in SHR; pharmacological blockade of the AT1R with losartan prevented collateral luminal expansion in WKY. In SHR control arteries, several mechano-sensitive and redox-dependent transcription regulators were down-regulated including Jun (-5.2X, P=0.02), Egr-1 (-4.1X, P=0.01), and NFkB1 (-1.95X, P=0.04). Predicted binding sites for NFkB and AP-1 were present in the genes altered in WKY but not SHR collaterals. Immunostaining demonstrated increased NFkB nuclear translocation in WKY but not SHR collaterals, and in collaterals of SHR treated with apocynin to restore a normal redox status. Based upon these results, we propose redox-dependent modulation of mechano-sensitive transcription factors as a mechanism to explain, at least in part, the fundamental differences in collateral gene expression between WKY and SHR and the impairment of collateral growth during chronic oxidative stress. Key words: arteriogenesis, microarray analysis, peripheral vascular disease, gene expression

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE19524 | GEO | 2010/12/15

SECONDARY ACCESSION(S): PRJNA122237

REPOSITORIES: GEO

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Project description:Background: The vascular wall of small arteries is heavily affected by high blood pressure. However, the underlying mechanisms causing vascular changes are not fully elucidated. Using a novel data-independent acquisition mass spectrometry (DIA-MS) approach, we aimed to determine the proteomic changes in small mesenteric arteries during early-onset high blood pressure in a rat model of hypertension. Methods: Snap frozen small mesenteric and renal arteries from the spontaneous hypertension rat (SHR) model and Wistar Kyoto (WKY) control rats were collected from two time points (6- and 12-weels of age) and analyzed by a label free quantitative DIA-MS workflow. Mesenteric arteries from Wister Hannover rats were included as an additional control to clarify genetic drift caused by selective inbreeding. Results: We identified a total of 3956 consistent proteins in the mesenteric artery wall and found that 286 proteins were significantly regulated in 12-weeks old SHRs compared to WKY controls. Comparing to an in silico matrisome database, we identified 38 extracellular matrix-associated proteins that could distinguish SHRs from WKY controls. Furthermore, when comparing the significantly regulated proteins identified in mesenteric and renal arteries, we identified 18 proteins, including Serpina3l, Igg-2a, ENSRNOG00000049829, Acyp2, Enpp3, Lss, Acaa1a, Basp1, an isoform of Basp1, Flot1, Flot2, Gstt1, Nit1, Ppid, Ikbkap, Poglut3, P4ha2 and Usp15, that were changed in both vascular beds. These proteins were associated with vital cellular processes, such as dyslipidemia, protease inhibition, remodeling and generation of reactive oxygen species. Majority of the identified proteins and pathways were associated with hypertension, and mapping the underlying changes help understanding the pathological processes occurring in the arterial wall during early-onset hypertension. Conclusions: Our data provides an in-depth analysis of the proteomic architecture of the mesenteric and renal artery wall from SHRs and WKY control rats. We identified 18 novel candidate proteins that highlights critical changes in small arteries of the SHR.

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Potential Molecular Basis for Impaired Collateral Artery Growth in the Spontaneously Hypertensive Rat

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