Abstract
SummaryAortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffening through their extracellular effects. Aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) vs. Wistar‐Kyoto (WKY) rats in vivo by echocardiography and ex vivo by isometric force measurements in isolated de‐endothelized aortic vessel segments. Vascular smooth muscle cells were isolated from thoracic aorta and embedded in a collagen I matrix in an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. SHR VSMCs increased the synthesis of collagen and induced collagen fibril disorganization in reconstituted vessels. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1‐ and bone morphogenetic protein 1 (BMP1)‐mediated proteolytic cleavage of lysyl oxidase (LOX). These VSMC‐induced alterations in the SHR were attenuated by an inhibitor of serum response factor (SRF)/myocardin. Therefore, SHR VSMCs exhibit extracellular dysregulation through modulating integrin β1 and BMP1/LOX via SRF/myocardin signaling in aortic stiffening.
Highlights
Aortic stiffening is a fundamental component of aging-related vascular diseases (McEniery, Wilkinson & Avolio, 2007; Wallace et al., 2007)
Given that our recent study revealed a pivotal role for upregulation of the serum response factor (SRF)/ myocardin pathway in pathological aortic stiffening (Zhou, Lee, Stoll, Ma, Costa, et al 2017; Zhou, Lee, Stoll, Ma, Wiener, et al 2017), we further explored possible links between SRF/myocardin and integrin/ lysyl oxidase (LOX) signaling in the extracellular regulation of stiffness by aortic vascular smooth muscle cells (VSMCs)
These characteristics of thoracic aorta (TA) VSMCs in hypertension have not been observed in vivo previously; our results provide new evidence showing that the phenotypic transformation of VSMCs is a key component of spontaneously hypertensive rats (SHRs) TA that contributes to aortic stiffening in hypertension
Summary
Aortic stiffening is a fundamental component of aging-related vascular diseases Our previous study successfully distinguished the role of VSMCs from the extracellular matrix (ECM) in aortic stiffness in vitro utilizing a three-dimensional (3D) tissue model reconstituted system consisting of isolated VSMCs and collagen (Qiu et al, 2010) This model provides the necessary simplicity to characterize interactions between VSMCs and the surrounding ECM and explore the molecular mechanisms mediating these changes. Given that our recent study revealed a pivotal role for upregulation of the serum response factor (SRF)/ myocardin pathway in pathological aortic stiffening (Zhou, Lee, Stoll, Ma, Costa, et al 2017; Zhou, Lee, Stoll, Ma, Wiener, et al 2017), we further explored possible links between SRF/myocardin and integrin/ LOX signaling in the extracellular regulation of stiffness by aortic VSMCs
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