Journal article
DDR1 (Discoidin Domain Receptor-1)-RhoA (Ras Homolog Family Member A) Axis Senses Matrix Stiffness to Promote Vascular Calcification
Arteriosclerosis, thrombosis, and vascular biology, Vol.40(7), pp.1763-1776
07/2020
DOI: 10.1161/ATVBAHA.120.314697
PMCID: PMC7310304
PMID: 32493168
Abstract
Objective: Vascular calcification is a pathology characterized by arterial mineralization, which is a common late-term complication of atherosclerosis that independently increases the risk of adverse cardiovascular events by fourfold. A major source of calcifying cells is transdifferentiating vascular smooth muscle cells (VSMCs). Previous studies showed that deletion of the collagen-binding receptor, DDR1 (discoidin domain receptor-1), attenuated VSMC calcification. Increased matrix stiffness drives osteogenesis, and DDR1 has been implicated in stiffness sensing in other cell types; however, the role of DDR1 as a mechanosensor in VSMCs has not been investigated. Here, we test the hypothesis that DDR1 senses increased matrix stiffness and promotes VSMC transdifferentiation and calcification. Approach and Results: Primary VSMCs isolated fromDdr1(+/+)(wild-type) andDdr1(-/-)(knockout) mice were studied on collagen-I-coated silicon substrates of varying stiffness, culturing in normal or calcifying medium. DDR1 expression and phosphorylation increased with increasing stiffness, as did in vitro calcification, nuclear localization of Runx2 (Runt-related transcription factor 2), and expression of other osteochondrocytic markers. By contrast, DDR1 deficient VSMCs were not responsive to stiffness and did not undergo transdifferentiation. DDR1 regulated stress fiber formation and RhoA (ras homolog family member A) activation through the RhoGEF (rho guanine nucleotide exchange factor), Vav2. Inhibition of actomyosin contractility reduced Runx2 activation and attenuated in vitro calcification in wild-type VSMCs. Finally, a novel positive feedforward loop was uncovered between DDR1 and actomyosin contractility, important in regulating DDR1 expression, clustering, and activation. Conclusions: This study provides mechanistic insights into DDR1 mechanosignaling and shows that DDR1 activity and actomyosin contractility are interdependent in mediating stiffness-dependent increases in VSMC calcification.
Details
- Title: Subtitle
- DDR1 (Discoidin Domain Receptor-1)-RhoA (Ras Homolog Family Member A) Axis Senses Matrix Stiffness to Promote Vascular Calcification
- Creators
- David Ngai - Ted Rogers Centre for Heart ResearchMarsel Lino - Ted Rogers Centre for Heart ResearchKatheryn E. Rothenberg - Ted Rogers Centre for Heart ResearchCraig A. Simmons - Ted Rogers Centre for Heart ResearchRodrigo Fernandez-Gonzalez - University of TorontoMichelle P. Bendeck - Ted Rogers Centre for Heart Research
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.40(7), pp.1763-1776
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/ATVBAHA.120.314697
- PMID
- 32493168
- PMCID
- PMC7310304
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Number of pages
- 14
- Grant note
- MOP133592 / Canadian Institutes of Health Research - Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR)
- Language
- English
- Date published
- 07/2020
- Academic Unit
- Biology
- Record Identifier
- 9984696580902771
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