Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition

Evandro M. Neto-Neves, Mary B. Brown, Maria V. Zaretskaia, Samin Rezania, Adam G. Goodwill, Brian P. McCarthy, Scott A. Persohn, Paul Territo, Jeffrey Kline

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor–dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

Original languageEnglish (US)
Pages (from-to)700-712
Number of pages13
JournalAmerican Journal of Pathology
Volume187
Issue number4
DOIs
StatePublished - Apr 1 2017

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Pulmonary Embolism
Microspheres
Pulmonary Hypertension
Vascular Endothelial Growth Factor A
Polystyrenes
Phenotype
Right Ventricular Function
Lung
Vascular Endothelial Growth Factor Receptor
Oxygen Consumption
Protein-Tyrosine Kinases
Hypertrophy
Plastics
Blood Vessels
Sprague Dawley Rats
Echocardiography
Semaxinib
Dilatation
Rodentia
Angiography

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition. / Neto-Neves, Evandro M.; Brown, Mary B.; Zaretskaia, Maria V.; Rezania, Samin; Goodwill, Adam G.; McCarthy, Brian P.; Persohn, Scott A.; Territo, Paul; Kline, Jeffrey.

In: American Journal of Pathology, Vol. 187, No. 4, 01.04.2017, p. 700-712.

Research output: Contribution to journalArticle

Neto-Neves, Evandro M. ; Brown, Mary B. ; Zaretskaia, Maria V. ; Rezania, Samin ; Goodwill, Adam G. ; McCarthy, Brian P. ; Persohn, Scott A. ; Territo, Paul ; Kline, Jeffrey. / Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition. In: American Journal of Pathology. 2017 ; Vol. 187, No. 4. pp. 700-712.
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