SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model

Research output: Contribution to journalArticle

Abstract

Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH. Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle. Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis. Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.

Original languageEnglish (US)
Article number123
JournalRespiratory research
Volume20
Issue number1
DOIs
StatePublished - Jun 17 2019

Fingerprint

Pulmonary Hypertension
Endothelial Cells
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
Cell Proliferation
Right Ventricular Hypertrophy
Vascular Endothelial Growth Factor Receptor
Semaxinib
Hypoxia
Transcriptome
Protein-Tyrosine Kinases
Rodentia
Flow Cytometry
Phosphorylation

Keywords

  • Angiogenesis
  • Cardiac endothelial cell
  • Pulmonary hypertension
  • Right ventricle
  • VEGFR-2

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model. / Peloquin, Grace L.; Johnston, Laura; Damarla, Mahendra; Damico, Rachel L; Hassoun, Paul M; Kolb, Todd Matthew.

In: Respiratory research, Vol. 20, No. 1, 123, 17.06.2019.

Research output: Contribution to journalArticle

@article{f4592a3cefaf4aea8080cc109082a9ea,
title = "SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model",
abstract = "Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a {"}master regulator{"} of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH. Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle. Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis. Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.",
keywords = "Angiogenesis, Cardiac endothelial cell, Pulmonary hypertension, Right ventricle, VEGFR-2",
author = "Peloquin, {Grace L.} and Laura Johnston and Mahendra Damarla and Damico, {Rachel L} and Hassoun, {Paul M} and Kolb, {Todd Matthew}",
year = "2019",
month = "6",
day = "17",
doi = "10.1186/s12931-019-1079-x",
language = "English (US)",
volume = "20",
journal = "Respiratory Research",
issn = "1465-9921",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model

AU - Peloquin, Grace L.

AU - Johnston, Laura

AU - Damarla, Mahendra

AU - Damico, Rachel L

AU - Hassoun, Paul M

AU - Kolb, Todd Matthew

PY - 2019/6/17

Y1 - 2019/6/17

N2 - Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH. Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle. Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis. Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.

AB - Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH. Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle. Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis. Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.

KW - Angiogenesis

KW - Cardiac endothelial cell

KW - Pulmonary hypertension

KW - Right ventricle

KW - VEGFR-2

UR - http://www.scopus.com/inward/record.url?scp=85067578194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067578194&partnerID=8YFLogxK

U2 - 10.1186/s12931-019-1079-x

DO - 10.1186/s12931-019-1079-x

M3 - Article

C2 - 31208454

AN - SCOPUS:85067578194

VL - 20

JO - Respiratory Research

JF - Respiratory Research

SN - 1465-9921

IS - 1

M1 - 123

ER -