Collectivization of Vascular Smooth Muscle Cells via TGF-β–Cadherin-11–Dependent Adhesive Switching

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Abstract

Objective—

Smooth muscle cells (SMCs) in healthy arteries are arranged as a collective. However, in diseased arteries, SMCs commonly exist as individual cells, unconnected to each other. The purpose of this study was to elucidate the events that enable individualized SMCs to enter into a stable and interacting cell collective.

Approach and Results—

Human SMCs stimulated to undergo programmed collectivization were tracked by time-lapse microscopy. We uncovered a switch in the behavior of contacting SMCs from semiautonomous motility to cell–cell adherence. Central to the cell-adherent phenotype was the formation of uniquely elongated adherens junctions, up to 60 μm in length, which appeared to strap adjacent SMCs to each other. Remarkably, these junctions contained both N-cadherin and cadherin-11. Ground-state depletion super-resolution microscopy revealed that these hybrid assemblies were comprised of 2 parallel nanotracks of each cadherin, separated by 50 nm. Blocking either N-cadherin or cadherin-11 inhibited collectivization. Cell–cell adhesion and adherens junction elongation were associated with reduced transforming growth factor-β signaling, and exogenous transforming growth factor-β1 suppressed junction elongation via the noncanonical p38 pathway. Imaging of fura-2–loaded SMCs revealed that SMC assemblies displayed coordinated calcium oscillations and cell–cell transmission of calcium waves which, together with increased connexin 43–containing junctions, depended on cadherin-11 and N-cadherin function.

Conclusions—

SMCs can self-organize, structurally and functionally, via transforming growth factor-β–p38–dependent adhesive switching and a novel adherens junction architecture comprised of hybrid nanotracks of cadherin-11 and N-cadherin. The findings define a mechanism for the assembly of SMCs into networks, a process that may be relevant to the stability and function of blood vessels.

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