Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.
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.
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Evandro M
EM
Neto-Neves
Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, Indiana.
Mary B
MB
Brown
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Maria V
MV
Zaretskaia
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Samin
S
Rezania
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Adam G
AG
Goodwill
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.
Brian P
BP
McCarthy
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.
Scott A
SA
Persohn
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.
Paul R
PR
Territo
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: jefkline@iupui.edu.
Jeffrey A
JA
Kline
D000818:Animals; D006332:Cardiomegaly / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D008863:Microspheres; D010101:Oxygen Consumption / Q000187:drug effects; D019007:P-Selectin / Q000097:blood; D010313:Partial Pressure; D010805:Physical Conditioning, Animal; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011137:Polystyrenes; D011655:Pulmonary Embolism / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000097:blood / Q000150:complications / Q000503:physiopathology
D007211:Indoles; D019394:Ki-67 Antigen; D019007:P-Selectin; D017395:Plasminogen Activator Inhibitor 1; D011137:Polystyrenes; D011758:Pyrroles; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib