Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat: Insight from microarray analysis

Joseph L. Unthank, Jeanette McClintick, Carlos A. Labarrere, Lang Li, Matthew R. Distasi, Steven Miller

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 NFκB1 (-1.95×, P = 0.04). Predicted binding sites for NFκB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFκB 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 NFκB as a potential mechanism.

Original languageEnglish (US)
Article numbere00005
JournalPhysiological Reports
Volume1
Issue number2
DOIs
StatePublished - 2013

Fingerprint

Inbred SHR Rats
Microarray Analysis
Arteries
Growth
Gene Expression
Oxidation-Reduction
Down-Regulation
Genes
Angiotensin Type 1 Receptor
Losartan
Transcription Factor AP-1
Small Interfering RNA
Signal Transduction
Nitric Oxide
Transcription Factors
Up-Regulation
Binding Sites
Cell Proliferation
Pharmacology

Keywords

  • Arteriogenesis
  • Collateral gene expression
  • Microarray analysis
  • Peripheral vascular disease

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology

Cite this

Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat : Insight from microarray analysis. / Unthank, Joseph L.; McClintick, Jeanette; Labarrere, Carlos A.; Li, Lang; Distasi, Matthew R.; Miller, Steven.

In: Physiological Reports, Vol. 1, No. 2, e00005, 2013.

Research output: Contribution to journalArticle

Unthank, Joseph L. ; McClintick, Jeanette ; Labarrere, Carlos A. ; Li, Lang ; Distasi, Matthew R. ; Miller, Steven. / Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat : Insight from microarray analysis. In: Physiological Reports. 2013 ; Vol. 1, No. 2.
@article{ac8525be259f4cff9f5db6ac70c2bb04,
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{\circledR} 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 NFκB1 (-1.95×, P = 0.04). Predicted binding sites for NFκB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFκB 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 NFκB as a potential mechanism.",
keywords = "Arteriogenesis, Collateral gene expression, Microarray analysis, Peripheral vascular disease",
author = "Unthank, {Joseph L.} and Jeanette McClintick and Labarrere, {Carlos A.} and Lang Li and Distasi, {Matthew R.} and Steven Miller",
year = "2013",
doi = "10.1002/phy2.5",
language = "English (US)",
volume = "1",
journal = "Physiological Reports",
issn = "2051-817X",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

TY - JOUR

T1 - Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat

T2 - Insight from microarray analysis

AU - Unthank, Joseph L.

AU - McClintick, Jeanette

AU - Labarrere, Carlos A.

AU - Li, Lang

AU - Distasi, Matthew R.

AU - Miller, Steven

PY - 2013

Y1 - 2013

N2 - 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 NFκB1 (-1.95×, P = 0.04). Predicted binding sites for NFκB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFκB 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 NFκB as a potential mechanism.

AB - 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 NFκB1 (-1.95×, P = 0.04). Predicted binding sites for NFκB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFκB 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 NFκB as a potential mechanism.

KW - Arteriogenesis

KW - Collateral gene expression

KW - Microarray analysis

KW - Peripheral vascular disease

UR - http://www.scopus.com/inward/record.url?scp=85008870526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008870526&partnerID=8YFLogxK

U2 - 10.1002/phy2.5

DO - 10.1002/phy2.5

M3 - Article

AN - SCOPUS:85008870526

VL - 1

JO - Physiological Reports

JF - Physiological Reports

SN - 2051-817X

IS - 2

M1 - e00005

ER -