Research ArticlePulmonary Arterial Hypertension

Cellular senescence impairs the reversibility of pulmonary arterial hypertension

See allHide authors and affiliations

Science Translational Medicine  29 Jul 2020:
Vol. 12, Issue 554, eaaw4974
DOI: 10.1126/scitranslmed.aaw4974

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Reversing maladaptive remodeling

Pathologic vascular remodeling of pulmonary arterial hypertension (PAH) associated with congenital heart disease in children can be reversed by shunt closure, which induces hemodynamic unloading, up to a point in time, but mechanisms driving the transition from reversible to irreversible vasculopathy remain poorly defined. Van der Feen et al. used a rodent model of monocrotaline- and aortocaval shunt–induced pulmonary hypertension with lung transplant to study the time course of reversibility of vascular remodeling. They demonstrated that cellular senescence was associated with late-stage, irreversible PAH and treatment with a senolytic could alter maladaptive vascular remodeling, suggesting a potential therapeutic target for patients with PAH.

Abstract

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.

View Full Text

Stay Connected to Science Translational Medicine