Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension

Abstract

Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…The model was associated with trending elevated RVSP measurements, which persisted from week 5 SuHx to week 8 SuHx. This is consistent with other reports using this model (Taraseviciene-Stewart et al, 2001;Boogard et al, 2009;Abe et al, 2010;Kunita-Takanezawa et al, 2014). The developmental hemodynamic elevations exhibited in this model are also representative of clinical presentation of PAH (Steele et al, 2010).…”

“…First described by Taraseviciene-Stewart and colleagues (Taraseviciene- Stewart et al, 2001), this model is premised on the involvement of vascular endothelial growth factor (VEGF) in the proper maintenance and differentiation of…”

Pathology of Pulmonary Hypertension

“…The potential role for early endothelial cell apoptosis in the pathogenesis of uncontrolled proliferation of pulmonary endothelial cells was first documented in the rat model of severe pulmonary hypertension caused by the combination of VEGF receptor blockade with SU5416 and chronic hypoxia [29]. Moreover, the role of endothelial cell apoptosis in the pathogenesis of PH was also extended to the monocrotaline model [30].…”

Hypoxia and chronic lung disease

“…Although the involvement of HIF in this phenotype and in disease severity has not yet been formally tested, it is conceivable that vascular cells have an altered hypoxia-sensing mechanism, predisposing them to increased growth potential and even genomic instability. In a model of severe PH in the rat, chronic hypoxia in association with chronic VEGF receptor inhibition with SU5416 may be critically involved in the initial endothelial cell death and selection of apoptosis-resistant proliferating cells, which obliterate the pulmonary arteries [57].…”