MEKK3-TGFβ crosstalk regulates inward arterial remodeling

Abstract

Arterial remodeling is an important adaptive mechanism that maintains normal fluid shear stress in a variety of physiologic and pathologic conditions. Inward remodeling, a process that leads to reduction in arterial diameter, plays a critical role in progression of such common diseases as hypertension and atherosclerosis. Yet despite its pathogenic importance, molecular mechanisms controlling inward remodeling remain undefined. Mitogen-activated protein kinases (MAPKs) perform a number of functions ranging from control of proliferation to migration and cell fate transitions. While the MAPK ERK1/2 signaling pathway has been extensively examined in the endothelium, less is known about the role of the MEKK3/ERK5 pathway in vascular remodeling. To better define the role played by this signaling cascade, we studied the effect of endothelial-specific deletion of its key upstream MAP3K, MEKK3, in adult mice. The gene’s deletion resulted in a gradual inward remodeling of both pulmonary and systematic arteries leading to spontaneous hypertension in both vascular circuits and accelerated progression of atherosclerosis in hyperlipidemic mice. Molecular analysis revealed activation of TGFβ signaling both in vitro and in vivo. Endothelial-specific TGFβR1 knockout prevented inward arterial remodeling in MEKK3 endothelial knockout mice. These data point to the unexpected participation of endothelial MEKK3 in regulation of TGFβR1-Smad2/3 signaling and inward arterial remodeling in artery diseases.SignificanceInward remodeling of arteries to reduce lumen diameter is a major factor in disease progression and morbidity in multiple vascular diseases, including hypertension and atherosclerosis. However, molecular mechanisms controlling inward arterial remodeling remain largely undefined. In this study, we identify endothelial MEKK3 as an unexpected regulator of inward remodeling via inhibition of TGFβ-Smad2/3 signaling. Genetic deletion of MEKK3 in adult endothelium results in induction of TGFβ-Smad2/3 signaling, endothelial-to-mesenchymal transition and inward remodeling in both pulmonary and arterial circuits. The latter process results in pulmonary and systemic hypertension and accelerates atherosclerosis. These results provide a new basis for understanding the inward artery remodeling that leads to reduced blood flow to affected tissues and exacerbates hypertension in vascular disease.

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

“…4). Inward remodeling was blocked by Alk5 ECKO (21), providing further support for the in vivo relevance of the pathway defined here. Alk5 ECKO also blocked the inward remodeling induced by low flow in the partial carotid ligation model (Fig.…”

“…The biphasic activation of Smad2/3 by flow suggests that another pathway activated at higher FSS antagonizes p-Smad2/3 nuclear translocation. The accompanying manuscript (21) reports that the ECKO of MEKK3 in mice triggers spontaneous inward arterial remodeling through the activation of the TGFβR1-Smad2/3 pathway. MEKK2 and MEKK3 are upstream components in the pathway that induces expression of the transcription factor Klf2 at high FSS (22).…”

“…Mice therefore received injections according to this regimen for 3 wk. Based on the accompanying paper (21), in which the lung vasculature was the most susceptible to remodeling after MEKK3 ECKO, we focused on this tissue. Examination of sections through the whole lung showed significantly increased smooth muscle actin (SMA) coverage of blood vessels (Fig.…”

“…Consistent with this model, the inhibition of CDK2 results in the activation of Smad2/3 in vitro and in vivo. However, at early times after the onset of flow, the depletion of MEKK3 The accompanying paper (21) reports that the EC-specific deletion of MEKK3 in mice activates Smad2/3 and induces drastic inward arterial remodeling, with resultant hypertension. This effect occurs first and most strongly in the pulmonary vasculature.…”

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

“…The latter two are reportedly involved in Hippo signaling (Jiang et al , 2020; Lu et al , 2021). Map3k3 is additionally involved in stress-activated protein kinase signaling and regulation of NFkB activation (Ellinger-Ziegelbauer et al , 1997; Yang et al , 2001), and recent studies show interaction with TGFβ signaling in arterial remodelling (Deng et al , 2021a; Deng et al , 2021b). Eight of the other thirteen genes encode components of G protein coupled receptor (GPCR) signaling pathways related to Cdc42 rho kinase that influences cytoskeletal regulation, cell adhesion and migration (Sakabe et al , 2017; Yoshida et al , 2021).…”