Janus face of vascular endothelial growth factor

The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension

Norbert F. Voelkel, Carlyne Cool, Laima Taraceviene-Stewart, Mark W. Geraci, Michael Yeager, Todd Bull, Michael Kasper, Rubin M. Tuder

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.

Original languageEnglish (US)
JournalCritical Care Medicine
Volume30
Issue number5 SUPPL.
StatePublished - 2002
Externally publishedYes

Fingerprint

Vascular Endothelium
Pulmonary Hypertension
Vascular Endothelial Growth Factor A
Endothelial Cells
Arteries
Lung
Vascular Endothelial Growth Factor Receptor
Survival
Apoptosis
Vascular Endothelial Growth Factor Receptor-2
Emphysema
Vascular Endothelial Growth Factor Receptor-1
Alveolar Epithelial Cells
Growth
Vasoconstriction
Pulmonary Artery
Lung Diseases
Blood Vessels
Cell Survival
Animal Models

Keywords

  • Apoptosis resistance
  • Endothelial cell phenotypes
  • Pulmonary circulation
  • Vascular endothelial growth factor
  • Vascular endothelial growth factor receptor blockade

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Janus face of vascular endothelial growth factor : The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. / Voelkel, Norbert F.; Cool, Carlyne; Taraceviene-Stewart, Laima; Geraci, Mark W.; Yeager, Michael; Bull, Todd; Kasper, Michael; Tuder, Rubin M.

In: Critical Care Medicine, Vol. 30, No. 5 SUPPL., 2002.

Research output: Contribution to journalArticle

Voelkel, Norbert F. ; Cool, Carlyne ; Taraceviene-Stewart, Laima ; Geraci, Mark W. ; Yeager, Michael ; Bull, Todd ; Kasper, Michael ; Tuder, Rubin M. / Janus face of vascular endothelial growth factor : The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. In: Critical Care Medicine. 2002 ; Vol. 30, No. 5 SUPPL.
@article{15cc3d3bd657425bb5593a1cc54a1a6b,
title = "Janus face of vascular endothelial growth factor: The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension",
abstract = "Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.",
keywords = "Apoptosis resistance, Endothelial cell phenotypes, Pulmonary circulation, Vascular endothelial growth factor, Vascular endothelial growth factor receptor blockade",
author = "Voelkel, {Norbert F.} and Carlyne Cool and Laima Taraceviene-Stewart and Geraci, {Mark W.} and Michael Yeager and Todd Bull and Michael Kasper and Tuder, {Rubin M.}",
year = "2002",
language = "English (US)",
volume = "30",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "5 SUPPL.",

}

TY - JOUR

T1 - Janus face of vascular endothelial growth factor

T2 - The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension

AU - Voelkel, Norbert F.

AU - Cool, Carlyne

AU - Taraceviene-Stewart, Laima

AU - Geraci, Mark W.

AU - Yeager, Michael

AU - Bull, Todd

AU - Kasper, Michael

AU - Tuder, Rubin M.

PY - 2002

Y1 - 2002

N2 - Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.

AB - Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.

KW - Apoptosis resistance

KW - Endothelial cell phenotypes

KW - Pulmonary circulation

KW - Vascular endothelial growth factor

KW - Vascular endothelial growth factor receptor blockade

UR - http://www.scopus.com/inward/record.url?scp=0036245561&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036245561&partnerID=8YFLogxK

M3 - Article

VL - 30

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 5 SUPPL.

ER -