Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

Abstract

Pulmonary arterial stiffness is an independent risk factor for mortality in pulmonary hypertension (PH) and plays a critical role in PH pathophysiology. Our laboratory has recently demonstrated arterial stiffening early in experimental PH, along with evidence for a mechanobiological feedback loop by which arterial stiffening promotes further cellular remodeling behaviors (Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suárez Velandia MM, Vitali S, Colas RA, Norris PC, Marinković A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Fredenburgh LE. 1: e86987, 2016). Cyclooxygenase-2 (COX-2) and prostaglandin signaling have been implicated in stiffness-mediated regulation, with prostaglandin activity inversely correlated to matrix stiffness and remodeling behaviors in vitro, as well as to disease progression in rodent PH models. The mechanism by which mechanical signaling translates to reduced COX-2 activity in pulmonary vascular cells is unknown. The present work investigated the transcriptional regulators Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1, a.k.a., TAZ), which are known drivers of downstream mechanical signaling, in mediating stiffness-induced changes in COX-2 and prostaglandin activity in pulmonary artery smooth muscle cells (PASMCs). We found that YAP/TAZ activity is increased in PAH PASMCs and experimental PH and is necessary for the development of stiffness-dependent remodeling phenotypes. Knockdown of YAP and TAZ markedly induces COX-2 expression and downstream prostaglandin production by approximately threefold, whereas overexpression of YAP or TAZ reduces COX-2 expression and prostaglandin production to near undetectable levels. Together, our findings demonstrate a stiffness-dependent YAP/TAZ-mediated positive feedback loop that drives remodeling phenotypes in PASMCs via reduced COX-2 and prostaglandin activity. The ability to interrupt this critical mechanobiological feedback loop and enhance local prostaglandin activity via manipulation of YAP/TAZ signaling presents a highly attractive novel strategy for the treatment of PH.

Basement Membrane Remodeling Controls Endothelial Function in Idiopathic Pulmonary Arterial Hypertension

“…Here, we observed that coating with type IV collagen had a stronger effect on YAP nuclear translocation in donor PAECs than in IPAH, as the latter, under basal conditions, already had increased YAP nuclear signal. Importantly in IPAH, increased YAP activation has been reported for other vascular cells, such as smooth muscle cells (5,43,44). Here, we show first evidence for a similar phenotype in PAECs.…”

Inflammatory Markers for Arterial Stiffness in Cardiovascular Diseases

“…The relationship between COX-2 and vascular remodeling was described in the pulmonary circulation. Pulmonary arterial stiffness occurs early in experimental pulmonary hypertension and is an independent risk factor for mortality in pulmonary hypertension ( 154 ). COX-2 is upregulated in pulmonary artery smooth muscle cells during hypoxia, associated with upregulation of the endothelin receptor ( 155 ) and intravascular macrophage accumulation ( 156 ).…”

“…COX-2 is upregulated in pulmonary artery smooth muscle cells during hypoxia, associated with upregulation of the endothelin receptor ( 155 ) and intravascular macrophage accumulation ( 156 ). The transcriptional regulator Yes-associated protein activity is increased in pulmonary hypertension in pulmonary artery smooth muscle cells and is necessary for development of stiffness-dependent remodeling phenotypes ( 154 ). However, selective COX-2 inhibition impairs the balance of vascular mediators, enables vascular hyperplasia, remodeling of the systemic vessels, platelet deposition, intravascular thrombosis, and is associated with several cardiovascular events ( 155 ).…”

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

“…Furthermore, in pulmonary vascular cells exposed to increasing extracellular matrix stiffness, a recently identified PH trigger (41), mechanoactivation of Yes-associated protein 1 (YAP) and the transcriptional coactivator with a PDZ-binding motif (TAZ, also known as WWTR1), induced the reductive enzyme glutaminase 1 (GLS1), thus promoting glutaminolysis and hyperproliferation (40). Glutaminolytic reprogramming was increased in the vascular lesions of PAH patients and animal models, and multiple vascular cell types in PH relied on the YAP/TAZ-GLS1 axis (42)(43)(44)(45). Pharmacologic inhibition of either YAP or GLS1 also effectively improved rodent PAH.…”