Abstract 507: Homotypic Interactions and Networking Among Vascular Smooth Muscle Cells Are Mediated by a Transforming Growth Factor-ß-Cadherin-11 Axis
Formation and stabilization of arteries requires that smooth muscle cells (SMCs) coalesce into sheets and layers of co-aligned cells. However, the molecular basis by which SMCs form a stable collective is largely unknown. To elucidate key steps in forming an ordered SMC collective, we tracked differentiation-competent human SMCs as they were induced to shift from individual behavior to collective patterning. Transmission electron microscopy identified the acquisition of well-developed adherens junctions during this transition. As well, immunofluorescence microscopy revealed both cadherin-2 and -11-containing intercellular junctions, the latter not previously identified in vascular SMCs. Furthermore, these junctions underwent striking elongation during collectivization (3-fold elongation, p<0.001), effectively strapping cells to each other. Adherens junction maturation was associated with down-regulation of phosphorylated SMAD2 and could be reversed by addition of transforming growth factor-beta (TGFß)1 (p<0.001). Time-lapse video microscopy revealed that collectivization of SMCs was partially inhibited by a blocking antibody to cadherin-2 (p=0.021) and strikingly inhibited by a cadherin-11 blocking antibody (p<0.001). Imaging of Fura2-loaded SMCs revealed coordinated calcium transients among stably contacting SMCs (p<0.001), but these were inhibited when cadherin-11 was blocked (p<0.001). Immunostaining of small and medium sized arteries in the mouse hindlimb identified OB-cadherin in both endothelial and SMC layers.
Conclusions: Cadherin-11 is present in the artery wall and mediates the acquisition of stable and functional homotypic interactions among contacting SMCs. This TGFß-regulatable phenomenon of collectivization could be critical to vascular development, repair, and regeneration.
Author Disclosures: B. Balint: None. H. Yin: None. J. Pickering: None.
- © 2014 by American Heart Association, Inc.