Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade

Soumitro Pal, M. Luisa Iruela-Arispe, V. Susan Harvey, Huiyan Zeng, Janice A. Nagy, Harold F. Dvorak, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis. Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division. To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay. RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors. RA also inhibited VPF/VEGF-induced phosphorylation of PLC-γ and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells. Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action. The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)112-120
Number of pages9
JournalMicrovascular Research
Volume60
Issue number2
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Tretinoin
Vascular Endothelial Growth Factor A
Blood Vessels
Endothelial cells
Retinoids
Endothelial Cells
Capillary Permeability
Fibroblast Growth Factor 2
Histamine
Cell Movement
Cell Differentiation
Phosphorylation
Angiogenesis Inducing Agents
Cell growth
Computer aided manufacturing
Transcription
Programmable logic controllers
Microvessels
Isomers
Cell Division

Keywords

  • Angiogenesis
  • CAM assay
  • cGMP
  • Miles assay
  • PLC-γ
  • Retinoic acid (RA)
  • Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)

ASJC Scopus subject areas

  • Biochemistry
  • Cardiology and Cardiovascular Medicine

Cite this

Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade. / Pal, Soumitro; Iruela-Arispe, M. Luisa; Harvey, V. Susan; Zeng, Huiyan; Nagy, Janice A.; Dvorak, Harold F.; Mukhopadhyay, Debabrata.

In: Microvascular Research, Vol. 60, No. 2, 2000, p. 112-120.

Research output: Contribution to journalArticle

Pal, Soumitro ; Iruela-Arispe, M. Luisa ; Harvey, V. Susan ; Zeng, Huiyan ; Nagy, Janice A. ; Dvorak, Harold F. ; Mukhopadhyay, Debabrata. / Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade. In: Microvascular Research. 2000 ; Vol. 60, No. 2. pp. 112-120.
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T1 - Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade

AU - Pal, Soumitro

AU - Iruela-Arispe, M. Luisa

AU - Harvey, V. Susan

AU - Zeng, Huiyan

AU - Nagy, Janice A.

AU - Dvorak, Harold F.

AU - Mukhopadhyay, Debabrata

PY - 2000

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N2 - All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis. Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division. To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay. RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors. RA also inhibited VPF/VEGF-induced phosphorylation of PLC-γ and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells. Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action. The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine. (C) 2000 Academic Press.

AB - All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis. Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division. To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay. RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors. RA also inhibited VPF/VEGF-induced phosphorylation of PLC-γ and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells. Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action. The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine. (C) 2000 Academic Press.

KW - Angiogenesis

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KW - Miles assay

KW - PLC-γ

KW - Retinoic acid (RA)

KW - Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)

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