Abstract
Epicardial formation involves the attachment of proepicardial (PE) cells to the heart and the superficial migration of mesothelial cells over the surface of the heart. Superficial migration has long been known to involve the interaction of integrins expressed by the epicardium and their ligands expressed by the myocardium; however, little is understood about signals that maintain the mesothelium as it migrates. One signaling pathway known to regulate junctional contacts in epithelia is the PI3K/Akt signaling pathway and this pathway can be modified by integrins. Here, we tested the hypothesis that the myocardially expressed, integrin ligand VCAM-1 modulates the activity of the PI3K/Akt signaling pathway by activating the lipid phosphatase activity of PTEN. We found that epicardial cells stimulated with a soluble form of VCAM-1 (sVCAM-1) reorganized PTEN from the cytoplasm to the membrane and nucleus and activated PTEN’s lipid phosphatase activity. Chick embryonic epicardial mesothelial cells (EMCs) expressing a shRNA to PTEN increased invasion in collagen gels, but only after stimulation by TGFβ3, indicating that loss of PTEN is not sufficient to induce invasion. Expression of an activated form of PTEN was capable of blocking degradation of junctional complexes by TGFβ3. This suggested that PTEN plays a role in maintaining the mesothelial state of epicardium and not in EMT. We tested if altering PTEN activity could affect coronary vessel development and observed that embryonic chick hearts infected with a virus expressing activated human PTEN had fewer coronary vessels. Our data support a role for VCAM-1 in mediating critical steps in epicardial development through PTEN in epicardial cells.
Highlights
Heart development involves the joining of various mesodermal and ectodermal cells to the mature organ
One pathway implicated in regulating epithelial junctional integrity is the PI3K/Akt signaling pathway [19,20,24] and this pathway can be modified by cell-surface integrins [19,25,26]
It is known that inhibition of PI3K/Akt signaling represses epicardial epicardial to mesenchymal transformation (EMT) in mice [22]
Summary
Heart development involves the joining of various mesodermal and ectodermal cells to the mature organ. The outermost mesothelial layer of the heart, the epicardium, is derived from elements of the splanchnic mesoderm, which first forms a villous structure protruding from the primitive liver called the proepicardium (PE) [1,2]. The PE attaches to the inner curvature of the looped myocardium and cells begin to superficially migrate over its surface to create a mesothelium called epicardium [1±3]. Concurrent with migration, and for some time after, epicardial mesothelial cells (EMCs) begin to delaminate and invade deeper aspects of the myocardium where they contribute to the coronary vessels, cardiac fibroblasts and AV valves [4±7]. Early sites of epicardial to mesenchymal transformation (EMT) are regionalized and most migrating mesothelial cells remain superficial until later. A simplistic model would be that while undergoing directional migration, EMCs are largely inhibited from undergoing EMT, once the mesothelium is established, other pathways stimulating EMC invasion become dominant
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
