Vicious cycle of hemodynamic perturbation and endothelial injury in development and progression of pulmonary arterial hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a devastating disease caused by loss of effective lung microvasculature for which there is no curative treatment. Evidence from preclinical models and human disease-causing genetic mutations point to endothelial cell (EC) injury and apoptosis as a central trigger for the initiation of PAH. However, how EC apoptosis leads to pulmonary hypertension (PH) and complex arteriolar remodeling is uncertain. Methods: Rats were subjected to SU5416-hypoxia (SUHx) and EC apoptosis, pulmonary vascular remodeling and arterial volume was assessed by immunohistochemistry, histology and microCT, respectively. Left pulmonary artery banding (LPAB) was performed, either 1 week before (prevention) or 5 weeks after SU injection (reversal), to study the effect of hemodynamic offloading. Results: In the SUHx model, EC apoptosis was markedly increased as early as 3 days post-SU, persisting through PAH development, and this was associated with a profound arterial pruning with reduction in lung arterial volume (~80%). LPAB abrogated lung EC apoptosis in the banded left lung and prevented as well as reversed arteriolar pruning. Moreover, in the reversal protocol, removal of the band at 10 weeks resulted in improvement in pulmonary hemodynamics and RV remodeling at 13 weeks. Conclusion: These data demonstrate that perturbed hemodynamic factors triggered by lung microvascular arteriolar loss play a requisite role in perpetuating endothelial injury in experimental PAH, leading to persistent arterial EC injury and disease progression. Importantly, vascular loss, arterial remodeling and PH are reversible once the cycle of perturbed hemodynamics and EC injury is broken by unilateral lung banding.

Emergence of disease-specific endothelial and stromal cell populations responsible for arterial remodeling during development of pulmonary arterial hypertension

“…Indeed, this EC population may be the link between perturbed pulmonary hemodynamics and complex arterial remodeling that was previously described. 6,52…”

“…Indeed, this EC population may be the link between perturbed pulmonary hemodynamics and complex arterial remodeling that was previously described. 6,52 At the 1 week timepoint, aAECs and dDECs exhibited a similar transcriptional signature characterized by the transient expression of genes related to cell proliferation and repair. However, at later time points (5 and 8 weeks), only aAECs exhibited a persistent dysfunctional gene expression profile that was consistent with dysregulated cell growth and reduced capacity for vascular repair and angiogenesis.…”