Background: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor
(VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and
chronic hypoxia, is known to have similar histological findings to those of PAH patients.
Objective: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress
with Sugen5416 in vivo.
Methods: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single
injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group).
Results: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day
14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration
was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive
RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia
group, associated with a significant increase of oxidative stress and TUNEL-positive cells in
both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium
was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of
VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed.
Conclusion: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to
accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.