Shear stress-exposed pulmonary artery endothelial cells fail to upregulate HSP70 in chronic thromboembolic pulmonary hypertension

Abstract

The pathophysiological mechanisms underlying chronic thromboembolic pulmonary hypertension (CTEPH) are still unclear. Endothelial cell (EC) remodeling is believed to contribute to this pulmonary disease triggered by thrombus and hemodynamic forces disbalance. Recently, we showed that HSP70 levels decrease by proatherogenic shear stress. Molecular chaperones play a major role in proteostasis in neurological, cancer and inflammatory/ infectious diseases. To shed light on microvascular responses in CTEPH, we characterized the expression of molecular chaperones and annexin A2, a component of the fibrinolytic system. There is no animal model that reproduces microvascular changes in CTEPH, and this fact led us to isolated endothelial cells from patients with CTEPH undergoing pulmonary endarterectomy (PEA). We exposed CTEPH-EC and control human pulmonary endothelial cells (HPAEC) to high- (15 dynes/cm2) or low- (5 dynes/cm2) shear stress. After high-magnitude shear stress HPAEC upregulated heat shock protein 70kDa (HSP70) and the HSP ER paralogs 78 and 94kDa glucose-regulated protein (GRP78 and 94), whereas CTEPH-ECs failed to exhibit this response. At static conditions, both HSP70 and HSP90 families in CTEPH-EC are decreased. Importantly, immunohistochemistry analysis showed that HSP70 expression was downregulated in vivo, and annexin A2 was upregulated. Interestingly, wound healing and angiogenesis assays revealed that HSP70 inhibition with VER-155008 further impaired CTEPH-EC migratory responses. These results implicate HSP70 as a novel master regulator of endothelial dysfunction in type 4 PH. Overall, we first show that global failure of HSP upregulation is a hallmark of CTEPH pathogenesis and propose HSP70 as a potential biomarker of this condition.

In situ Pulmonary Artery Thrombosis: A Previously Overlooked Disease

“…Further, the angiostatic factors have been shown to disturb calcium homeostasis and induce endothelial cell dysfunction ( Zabini et al, 2012 ). In addition, the high shear stress and pressure produced by redirected blood flow at unobstructed pulmonary vessels induce phenotypic changes and dysfunction of pulmonary vascular endothelial cells ( Simonneau et al, 2017 ; Salibe-Filho et al, 2020 ). The endothelial cell dysfunction then stimulates secretion of inflammatory factors, such as fibroblast growth factor-2 and adhesion molecules, promoting proliferation of vascular smooth muscle cells and vascular remodeling ( Mercier et al, 2017 ).…”

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

“…17 Since LPAB will not only reduce pulmonary blood flow, but also arterial pressure as a result of pressure loss across the flow limiting stenosis, it is not possible to separate their relative contributions to the protection of the lung arterial bed. Nonetheless, there is an abundant evidence to support the role of pathological levels of intimal shear stress in the pathogenesis of CHD related PAH, including promoting endothelial dysfunction 32 and abnormalities in EC adaptation. 33, 34 However, the role of pathological intimal shear stress in inducing EC injury and apoptosis is less clear.…”

Is pulmonary arterial hypertension associated with schistosomiasis distinct from pulmonary arterial hypertension associated with portal hypertension?

“… 9 This results in systemic vasodilation and increased cardiac output, which has been hypothesized to increase pulmonary vascular shear stress, resulting in endothelial cell injury and vascular remodeling. 10 , 11 It is estimated 2% to 10% of those with portal hypertension develop PoPAH. 12 Polymorphisms in estrogen metabolism genes and greater plasma levels of estrogen pathway metabolites correlate with the development of PoPAH in those at risk.…”