Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver

Abstract

Donor organ damage caused by cold preservation is a major problem affecting liver transplantation. Cold preservation most easily damages liver sinusoidal endothelial cells (LSECs), and information about the molecules modulating LSECs function can provide the basis for new therapeutic strategies. Adrenomedullin (AM) is a peptide known to possess anti-apoptotic and anti-inflammatory properties. AM is abundant in vascular endothelial cells, but levels are comparatively low in liver, and little is known about its function there. In this study, we demonstrated both AM and its receptors are expressed in LSECs. AM treatment reduced LSECs loss and apoptosis under cold treatment. AM also downregulated cold-induced expression of TNF, IL1, IL6, ICAM1 and VCAM1. AM reduced apoptosis and expression of ICAM1 and VCAM1 in an in vivo liver model subjected to cold storage. Conversely, apoptosis was exacerbated in livers from AM and RAMP2 (AM receptor activity-modifying protein) knockout mice. These results suggest that AM expressed in LSECs exerts a protective effect against cold-organ damage through modulation of apoptosis and inflammation.

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

“…We recently reported that the expression of adhesion markers was downregulated by AM. 36 In the absence of AM signaling in RAMP2-deficient ECs in the present study, these inflammatory adhesion molecules were upregulated, facilitating the attachment of macrophages. This inflammatory response, along with the partial detachment of ECs from the basement membrane, likely accelerates the attachment, transmigration, and accumulation of inflammatory cells within the vascular wall.…”

Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia

“…We also reported that AM+/− mice showed reduced blood flow and capillary formation in tumor transplantation and hind-limb ischemia models [6]. AM possesses novel angiogenic properties mediated by its ability to enhance VEGF expression [7]. However, during the chronic phase after BCAS, we detected no change in VEGF expression (data not shown).…”

Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models

“…This study further indicates that AM may help to protect against the progression of atherosclerosis, but the exact mechanism for this action remains to be understood. Expression of adhesion molecules in LECs [89] as well as liver sinusoidal endothelial cells [90] were reduced in response to AM treatment. Similar results were seen with VEGF-treated HUVECs [91].…”

“…In the sinusoidal endothelial cells of the liver, AM helps to protect these cells from cold injury during the process of cold preservation for a liver transplant by decreasing endothelial cell apoptosis and inflammation [90]. Conversely, in Adm +/- and Ramp2 +/ - mice there is increased apoptosis of the sinusoidal endothelial cells in the liver after cold injury [90] further indicating that AM signaling helps to regulate apoptosis. Wound healing is an essential physiological process that requires angiogenesis and lymphangiogenesis for proper healing.…”