Mechanisms of the Osteogenic Switch of Smooth Muscle Cells in Vascular Calcification: WNT Signaling, Bmps, Mechanotransduction, and Endmt
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bioengineering Review Mechanisms of the Osteogenic Switch of Smooth Muscle Cells in Vascular Calcification: WNT Signaling, BMPs, Mechanotransduction, and EndMT John Tyson, Kaylee Bundy, Cameron Roach, Hannah Douglas, Valerie Ventura, Mary Frances Segars, Olivia Schwartz and C. LaShan Simpson * Department of Agricultural and Biological Engineering, Mississippi State University, Starkville, MS 39762, USA; [email protected] (J.T.); [email protected] (K.B.); [email protected] (C.R.); [email protected] (H.D.); [email protected] (V.V.); [email protected] (M.F.S.); [email protected] (O.S.) * Correspondence: [email protected]; Tel.: +1-(662)-325-8279 Received: 30 June 2020; Accepted: 1 August 2020; Published: 6 August 2020 Abstract: Characterized by the hardening of arteries, vascular calcification is the deposition of hydroxyapatite crystals in the arterial tissue. Calcification is now understood to be a cell-regulated process involving the phenotypic transition of vascular smooth muscle cells into osteoblast-like cells. There are various pathways of initiation and mechanisms behind vascular calcification, but this literature review highlights the wingless-related integration site (WNT) pathway, along with bone morphogenic proteins (BMPs) and mechanical strain. The process mirrors that of bone formation and remodeling, as an increase in mechanical stress causes osteogenesis. Observing the similarities between the two may aid in the development of a deeper understanding of calcification. Both are thought to be regulated by the WNT signaling cascade and bone morphogenetic protein signaling and can also be activated in response to stress. In a pro-calcific environment, integrins and cadherins of vascular smooth muscle cells respond to a mechanical stimulus, activating cellular signaling pathways, ultimately resulting in gene regulation that promotes calcification of the vascular extracellular matrix (ECM). The endothelium is also thought to contribute to vascular calcification via endothelial to mesenchymal transition, creating greater cell plasticity. Each of these factors contributes to calcification, leading to increased cardiovascular mortality in patients, especially those suffering from other conditions, such as diabetes and kidney failure. Developing a better understanding of the mechanisms behind calcification may lead to the development of a potential treatment in the future. Keywords: vascular calcification; smooth muscle cells; canonical WNT; RUNX2; BMPs; integrins; cadherins; EndMT 1. Introduction Mechanical influence over tissue homeostasis is a predominant feature in bone formation and maintenance, acting as a promoter and regulator [1,2]. If the regulatory functions controlling the development of the bone matrix become overwhelmed, such as in the case of tissue injury, mineralization of soft tissue systems becomes a lethal phenomenon, commonly known as ectopic calcification [3]. An ever-increasing prevalence of mineralization is being recognized, specifically in vascular tissues. Vascular calcification is a comorbid pathology alongside obesity, diabetes, and chronic kidney disease. The buildup of hydroxyapatite crystals in various arterial layers, notably the tunica media (Figure1), promotes hypertension, atherosclerotic plaque burden, and the erosion of arterial tissue compliance and elastance on arteries [4]. There are many regulatory bone formation and structural proteins that are expressed in the calcified medial arterial layers and atherosclerotic plaques, which suggest that this Bioengineering 2020, 7, 88; doi:10.3390/bioengineering7030088 www.mdpi.com/journal/bioengineering Bioengineering 2020, 7, 88 2 of 23 Bioengineering 2020, 7, x FOR PEER 2 of 24 plaques,is an active which process suggest [5]. that The this process is an originates active process from [5] vascular. The process smooth originates muscle cells from (VSMCs) vascular that smooth have muscleundergone cells a(VSMCs) phenotypic that switch have undergone into osteoblast-like a phenotypic cells. switch Unlike into other osteoblast smooth muscle-like cells. cells, Unlike VSMCs other can smoothchange phenotypemuscle cells, due VSMCs to their can plasticity change [6 phenotype,7]. Originating due asto mesenchymaltheir plasticity stem [6,7] cells,. 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In the eventthat the of osteoblast arterial matrix-like differentiation, will be converted it is into suggested bone-like that matrix, the arterial forming matrix a region will be of gradualconverted plaque into bonegrowth.-like Under matrix, conditions forming a of region excessive of gradual strain, these plaque regions growth. could Under begin conditions to grow into of excessive calcified plaques, strain, theseoverwhelming regions could regulatory begin agents. to grow Such into agents calcified are interconnected plaques, overwhelming through the regulatory canonical WNT agents. signaling Such agentscascade, are one interconnected of the body’s through primary the structural canonical pathways WNT signali [18–20ng]. cascade, Runt-related one of transcription the body’s primary factor 2 structural(RUNX2) pathways is the primary [18–20] transcription. Runt-related factor transcription responsible factor for this 2 (RUNX2) phenotypic is the shift primary and is transcription a target gene factorof the responsible WNT cascade for [this21]. phenotypic This cascade shift is ubiquitousand is a target across gene the of body the WNT and evidentlycascade [21] controls. This cascade various isstructural ubiquitous processes. across the During body and WNT-based evidently controls osteogenesis, various studies structural have processes. demonstrated During a linkWNT between-based osteogenesis,matrix receptors studies known have as demonstrated integrins, cell-to-cell a link between receptors matrix known receptors as cadherins, known as and integrins, a set of cell growth-to- cell receptors known as cadherins, and a set of growth factors known as bone morphogenetic proteins factors known as bone morphogenetic proteins (BMPs) [19,22]. Under stiff matrix conditions and (BMPs) [19,22]. Under stiff matrix conditions and mechanical stress, specifically tension, these mechanical stress, specifically tension, these proteins potentially synergize with the WNT cascade to proteins potentially synergize with the WNT cascade to induce further osteogenesis through RUNX2 induce further osteogenesis through RUNX2 in arterial tissues, possibly increasing calcification [23–25]. in arterial tissues, possibly increasing calcification [23–25]. In addition to VSMCs, the underlying In addition to VSMCs, the underlying endothelium also contributes to vascular calcification via endothelium also contributes to vascular calcification via endothelial to mesenchymal transition. endothelial to mesenchymal transition. Understanding each of these mechanisms and their role in Understanding each of these mechanisms and their role in promoting calcification may help lead to promoting calcification may help lead to a targeted treatment in the future. a targeted treatment in the future. Figure 1. The structure of an artery wall. VSMCs are located in the tunica media, while endothelial Figure 1. The structure of an artery wall. VSMCs are located in the tunica media, while endothelial cells are mostly in the tunica intima [26]. cells are mostly in the tunica intima [26]. 2. Phenotypic Switch 2. Phenotypic Switch During vascular calcification, VSMCs are believed to undergo a phenotypic switch to osteoblast-like cells.During The exact vascular mechanism calcification, that initiates VSMCs the are phenotypic believed to switch undergo is unknown, a phenotypic but many switch studies to osteoblast research- like cells. The exact mechanism that initiates the phenotypic