Extra cellular matrix synthesis and tissue mechanics: Vascular remodeling, mechanism and disease

Vascular grafts were engineered using Small Intestinal Submucosa (SIS)-fibrin hybrid scaffold and implanted interpositionally into the arterial circulation of an ovine model. We sought to demonstrate implantability of SIS-Fibrin based grafts; examine the remodeling; and determine whether the presence of vascular cells in the medial wall was necessary for cellular infiltration from the host and successful remodeling of the implants. We observed no occlusions or anastomotic complications in 18 animals that received these grafts. Notably, the grafts exhibited unprecedented levels of host cell infiltration that was not limited to the anastomotic sites but occurred through the lumen as well as the extramural side, leading to uniform cell distribution. Incoming cells remodeled the extracellular matrix and matured into functional smooth muscle cells as evidenced by expression of myogenic markers and development of vascular reactivity. Although these results demonstrate that SIS-Fibrin grafts can be successfully implanted into the arterial circulation of a clinically relevant animal model, the mechanism why which cell-cell contacts control ECM synthesis was not understood during graft remodeling. Cell- cell contacts through Cadherin-11 (CDH11) regulates collagen and elastin synthesis both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11 null mouse model, we observed a significant reduction in the mechanical properties of Cdh11-/- as compared to WT (wild type) mouse tissues, such as aorta, bladder and skin. The deterioration of mechanical properties was accompanied by reduced collagen and elastin content in Cdh11-/- mouse tissues as well as cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-beta and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of key transcription factors, MRTF-A and MYOCD, led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating ECM synthesis with implications for many important biological processes including maintenance of tissue integrity, wound healing and tissue regeneration.