Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1

Brian D. Kelly, Sean F. Hackett, Kiichi Hirota, Yuji Oshima, Zheqing Cai, Shannon Berg-Dixon, Ashley Rowan, Zhijiang Yan, Peter A Campochiaro, Gregg L Semenza

Research output: Contribution to journalArticle

Abstract

Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1α-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1α is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.

Original languageEnglish (US)
Pages (from-to)1074-1081
Number of pages8
JournalCirculation Research
Volume93
Issue number11
DOIs
StatePublished - Nov 28 2003

Fingerprint

Hypoxia-Inducible Factor 1
Angiogenesis Inducing Agents
Angiopoietin-1
Intercellular Signaling Peptides and Proteins
Gene Expression
Proto-Oncogene Proteins c-sis
Vascular Endothelial Growth Factor A
Adenoviridae
Cell Hypoxia
Embryonic Stem Cells
Blood Vessels
Messenger RNA
Injections

Keywords

  • Angiogenesis
  • Gene therapy
  • Hypoxia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1. / Kelly, Brian D.; Hackett, Sean F.; Hirota, Kiichi; Oshima, Yuji; Cai, Zheqing; Berg-Dixon, Shannon; Rowan, Ashley; Yan, Zhijiang; Campochiaro, Peter A; Semenza, Gregg L.

In: Circulation Research, Vol. 93, No. 11, 28.11.2003, p. 1074-1081.

Research output: Contribution to journalArticle

Kelly, Brian D. ; Hackett, Sean F. ; Hirota, Kiichi ; Oshima, Yuji ; Cai, Zheqing ; Berg-Dixon, Shannon ; Rowan, Ashley ; Yan, Zhijiang ; Campochiaro, Peter A ; Semenza, Gregg L. / Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1. In: Circulation Research. 2003 ; Vol. 93, No. 11. pp. 1074-1081.
@article{5298570798f74804a1d2ae1dae5f5796,
title = "Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1",
abstract = "Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1α-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1α is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.",
keywords = "Angiogenesis, Gene therapy, Hypoxia",
author = "Kelly, {Brian D.} and Hackett, {Sean F.} and Kiichi Hirota and Yuji Oshima and Zheqing Cai and Shannon Berg-Dixon and Ashley Rowan and Zhijiang Yan and Campochiaro, {Peter A} and Semenza, {Gregg L}",
year = "2003",
month = "11",
day = "28",
doi = "10.1161/01.RES.0000102937.50486.1B",
language = "English (US)",
volume = "93",
pages = "1074--1081",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1

AU - Kelly, Brian D.

AU - Hackett, Sean F.

AU - Hirota, Kiichi

AU - Oshima, Yuji

AU - Cai, Zheqing

AU - Berg-Dixon, Shannon

AU - Rowan, Ashley

AU - Yan, Zhijiang

AU - Campochiaro, Peter A

AU - Semenza, Gregg L

PY - 2003/11/28

Y1 - 2003/11/28

N2 - Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1α-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1α is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.

AB - Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1α-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1α is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.

KW - Angiogenesis

KW - Gene therapy

KW - Hypoxia

UR - http://www.scopus.com/inward/record.url?scp=0344874751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0344874751&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000102937.50486.1B

DO - 10.1161/01.RES.0000102937.50486.1B

M3 - Article

C2 - 14576200

AN - SCOPUS:0344874751

VL - 93

SP - 1074

EP - 1081

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 11

ER -