Shear Stress Maladaptation in Pulmonary Arterial Hypertension. An Ageless Concept

Abstract

Despite significant improvement in our understanding of mechanisms involved in pulmonary artery remodeling in pulmonary arterial hypertension (PAH), the actual course of events leading to this devastating disease remains enigmatic. Indeed, several conditions have been shown to predispose to PAH, including epigenetic modifications (1, 2), genetic mutations, autoimmune and inflammatory conditions, drugs and toxins, and cardiac defects associated with increased pulmonary blood flow and/or pressure. Importantly, none of them appears to be sufficient on its own to lead to overt PAH, commanding the "multiple hits" theory, triggering and perpetuating the intense pulmonary vasculopathy leading to PAH. Intriguingly, despite highly heterogeneous initial triggers, pulmonary vessels respond very stereotypically in a manner similar to acute respiratory distress syndrome, in which variable initial lung injuries ultimately lead to strikingly homogeneous lung pathology (3). This stereotypic vascular response in PAH includes the formation of complex cellular and fibrotic intimal lesions, smooth muscle cells' proliferation, and apoptosis resistance, as well as adventitial infiltration and thickening (4). During the last decades, our understanding of the mechanisms involved in the endothelial dysfunction and the cancer-like angioproliferation in PAH has increased substantially from genetic, epigenetic, metabolic, and inflammatory abnormalities that contribute to this pulmonary vascular remodeling (5). Interestingly, the role of disturbed pulmonary blood flow and the concomitant shear stress, recognized early on as a risk factor for pulmonary vascular injury and remodeling (6), has now been reacknowledged.In this issue of the Journal, Szulcek and colleagues (pp. 1410-1420) demonstrate that human pulmonary artery endothelial cells (PAEC) isolated from subpleural lung microcirculation of patients with PAH at the time of transplantation or necropsy and submitted to ex vivo high shear stress exhibited delayed morphological adaptation compared with control PAEC (7). Interestingly, proximal PAH-PAEC exhibited normal shear stress-related adaptation, confirming the phenotypic heterogeneity of PAEC within the pulmonary vascular bed in PAH (8). At the microcirculation level, platelet endothelial cell adhesion molecule (PECAM)-1 expression and activation of its signaling mediators (extracellular signal-regulated kinases, SRC, and caveolin 1) were significantly decreased in PAH. PECAM-1 expression was not only reduced but was distributed unevenly, with areas entirely lacking the junctional protein, especially in areas of nonuniform flow. Conversely, PECAM-1 independent shear-responsive kinases and PECAM-1 mRNA were normally expressed in PAH-PAEC, suggesting intact shear stress sensing, but specific alterations in PECAM-1 signaling post-transcriptionally presumably related to caspase-mediated cleavage of PECAM-1. The aberrant morphological adaptation to shear stress was reproduced in control PAEC by silencing of PECAM-1, whereas inhibiting caspa...

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

“…Similarly, in vitro steady shear stress flow patterns could be generated by various types of dedicated apparatus to deliver a specific, unidirectional, and constant flow rate across a cultured endothelial monolayer in a geometrically uniform flow chamber. Various levels of shear stress could be applied to pulmonary microvascular endothelial cell monolayers, ranging from physiological (2.5 dyn/cm 2 ) to high shear (15 or ultimately 21 dyn/cm 2 ), and maintained up to 72 hours or increased gradually with various flow profiles at intervals of 24 hours (37,38). Finally, the availability of coculture technology could also be useful when answering specific biological questions and for studying both physiological and pathophysiological interactions between different cell populations (e.g., immune cells with PASMCs) (39).…”

Acquired von Willebrand syndrome (AVWS) type 2, characterized by decreased high molecular weight multimers, is common in children with severe pulmonary hypertension (PH)

“…The pathobiology of pulmonary arterial hypertension (PAH) is a complex and multifactorial process, in which peripheral artery loss and obstructive vascular remodeling cause a rise in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), resulting in progressive right heart failure and death ( 21 ). Inflammation, delayed shear adaptation and endothelial cell dysfunction seem to play crucial roles in this process ( 22 – 25 ). Wall shear stress-dependent changes in pulmonary arterial lumen diameter were found to be a persistent remodeling response ( 26 ).…”

Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application

“…Arterial remodeling in PAH causes narrowing of the pulmonary arteries/arterioles and the shear-stress resulting from blood flow exacerbates arterial remodeling. 22 We thus investigated the influence of fluid-induced shear stress (low, medium and high, Fig. 4A ) on the cellular communication and orientation of the cells on the chips.…”