Regulation of endothelial and epithelial barrier functions by peptide hormones of the adrenomedullin family

Abstract

The correct regulation of tissue barriers is of utmost importance for health. Barrier dysfunction accompanies inflammatory disorders and, if not controlled properly, can contribute to the development of chronic diseases. Tissue barriers are formed by monolayers of epithelial cells that separate organs from their environment, and endothelial cells that cover the vasculature, thus separating the blood stream from underlying tissues. Cells within the monolayers are connected by intercellular junctions that are linked by adaptor molecules to the cytoskeleton, and the regulation of these interactions is critical for the maintenance of tissue barriers. Many endogenous and exogenous molecules are known to regulate barrier functions in both ways. Proinflammatory cytokines weaken the barrier, whereas anti-inflammatory mediators stabilize barriers. Adrenomedullin (ADM) and intermedin (IMD) are endogenous peptide hormones of the same family that are produced and secreted by many cell types during physiologic and pathologic conditions. They activate certain G-protein-coupled receptor complexes to regulate many cellular processes such as cytokine production, actin dynamics and junction stability. In this review, we summarize current knowledge about the barrier-stabilizing effects of ADM and IMD in health and disease.

Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease)

“…Cellular receptors for ADM consist of the corticotropin releasing hormone like receptor, which has several endogenous ligands, complexed to co-receptors of the receptor activity modify protein (RAMP) family. 17 We analyzed expression of RAMP2 by qPCR in BOECs and monocytes as this co-receptor for CRLR is most specific for ADM. 18 However, we found no significant difference in RAMP2 expression in SCLS and healthy donor-derived cells, either at baseline or in response to proinflammatory stimuli (Figure S3). These results demonstrate that blood monocytes and ECs are both sources of ADM and that monocytes and ECs from SCLS patients have heightened responses to inflammatory stimuli compared to those from healthy subjects despite comparable receptor expression.…”

Endothelial cells and SARS-CoV-2: An intimate relationship

“…In response to a viral infection, epithelial cells signal to the endothelium, which starts the recruitment of cells from the immune system, in a highly temporally regulated process [ 51 ]. Endothelium and epithelium, form a cell monolayer connected by tight junctions (TJ), which regulate the permeability of the monolayer and adherent junctions (AJ) that mediate intercellular adhesion interactions [ 52 , 53 ]. The pulmonary endothelium consists of macro and microvascular EC [ 54 ].…”

Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first‐in‐human study and during experimental human endotoxaemia in healthy subjects

“…Adrenomedullin (ADM) is a free circulating peptide hormone, which is involved in the regulation of vascular tone and stabilization of the endothelial barrier . During sepsis and most pronounced during septic shock, elevated concentrations of circulating ADM are observed, which correlate with disease severity and mortality .…”