Dataset Information

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??M) 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.

SUBMITTER: Peloquin GL

PROVIDER: S-EPMC6580559 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Peloquin Grace L GL Johnston Laura L Damarla Mahendra M Damico Rachel L RL Hassoun Paul M PM Kolb Todd M TM

Respiratory research 20190617 1

<h4>Background</h4>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 attenua ...[more]

PMID: 31208454

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Dataset Information

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

Background

Methods

Result

Conclusions

Publications

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

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