Cadherin-11 in Cardiovascular Mechanobiology: Altered Immune Response and Endothelial Contractility
Johnson, Camryn Leigh
Cadherin-11 (CDH11) is a cell-cell adhesion protein that has been implicated in several diseases associated with fibrosis and inflammation. The bulk of current CDH11 research focuses on fibroblasts and its upregulation during myofibroblast differentiation; however, it has been shown to be expressed by a wide range of cell types. This dissertation sought to examine the role of CDH11 in macrophages and endothelial cells during cardiovascular disease progression. Cardiovascular disease is the leading cause of death in the world, and two major diseases constituting that health burden are atherosclerosis and calcific aortic valve disease (CAVD). Atherosclerosis progression involves an ongoing inflammatory response, with macrophages working in conjunction with T cells to perpetuate inflammation and degrade the extracellular matrix of the plaque. The most common clinical manifestation of atherosclerosis is plaque rupture, and more vulnerable plaques have higher macrophage contents. We showed that, although Cdh11 expression correlated with markers of plaque inflammation, a global loss of Cdh11 in fact increased plaque inflammation. However, we also determined that a loss of Cdh11 resulted in an altered atherosclerotic immune response. We demonstrated that Cdh11-deficient macrophages exhibited impaired migration and decreased cortical tension, despite a compensatory upregulation of migration-related genes. These results indicate that CDH11 can have a profound impact on the inflammatory response and on the functional behavior of macrophages. CAVD is a cardiac disease which has an already proven relationship to CDH11, with CDH11 expression upregulated in human calcified valves. Although primarily driven by aortic valve interstitial cells, aortic valve endothelial cells (AVECs) have been shown to have an impact on disease progression as well. We determined that AVECs isolated from the aorta-facing side of the valve, the site of preferential clinical calcification formation, expressed significantly more CDH11 compared to the ventricle-facing side. Aorta-facing AVECs also exhibited increased contraction, both in single- and co-culture with interstitial cells. These results pose one possible pathway through which CDH11 could impact AVECs and their contribution to the development of calcification. Together, the findings in this dissertation illustrate the importance of CDH11 both in the inflammatory response and in cellular functions in macrophages and endothelial cells.