Aims: 

Intermedin (IMD) is a novel member of calcitonin-gene-related-peptide family which acts via increased production of cAMP via calcitonin-receptor-like-receptors (CRLR). The main objective of the present study was to analyze the molecular mechanisms of differential effects of IMD on macromolecule permeability of endothelial cells of different vascular beds.

Methods and Results: 

Here we demonstrate that IMD increases permeability of rat coronary microvascular endothelial cells (RCEC) and reduces permeability of human umbilical vein endothelial cells (HUVEC). These IMD effects are CRLR and cAMP-dependent. IMD causes a derangement of actin cytoskeleton accompanied by loss of VE-cadherin in RCEC, while it causes a rearrangement of actin cytoskeleton and VE-cadherin at cell-cell junctions in HUVEC. IMD inactivates RhoA/Rock pathway in both cell types; however, it inactivates Rac1 in RCEC, while activating Rac1 in HUVEC. Inhibition of RhoA/Rock pathway in RCEC but not in HUVEC resulted in inactivation of Rac1, derangement of actin cytoskeleton, and loss of barrier function.

Conclusion: 

The data of present study demonstrate that IMD has differential effect on permeability of RCEC and HUVEC. This differential effect of IMD is due to differential regulation of actin cytoskeleton dynamics and Rac1 activity. Moreover, Rac1 activity is regulated by RhoA/Rock pathway in RCEC but not in HUVEC.