Decoy Receptor CXCR7 Modulates Adrenomedullin-Mediated Cardiac and Lymphatic Vascular Development

Abstract

Summary Atypical 7-transmembrane receptors, often called decoy receptors, act promiscuously as molecular sinks to regulate ligand bioavailability and consequently temper the signaling of canonical G protein-coupled receptor (GPCR) pathways. Loss of mammalian CXCR7, the most recently described decoy receptor, results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. Here, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin (Adm = gene, AM = protein)—a mitogenic peptide-hormone required for normal cardiovascular development—is tightly controlled by CXCR7. To this end, Cxcr7−/− mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes which can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7−/− mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiac and vascular development.

Adrenomedullin in lymphangiogenesis: from development to disease

“…2a). These data suggest that, in the absence of the decoy receptor, an excess of AM leads to hyperproliferation of LECs and subsequently enlarged, poorly formed lymphatic sacs [25]. Further examination of LECs in vitro and lymphatic beds in vivo confirmed the ability of CXCR7 to affect the lymphatic endothelium.…”

“…Because of the close proximity of and complex connections between the lymphatic and blood vasculatures, it is possible that expression of Adm, Calcrl, and Ramp2 by both BECs and LECs has effects not only in their own microenvironments, but also in the adjacent vascular tissue. Recent studies from our lab have substantiated this hypothesis, definitively identifying CXCR7 as a potent modulator of AM signaling and AM-mediated lymphangiogenesis [25].…”

“…Further examination of LECs in vitro and lymphatic beds in vivo confirmed the ability of CXCR7 to affect the lymphatic endothelium. When treated with AM, cultured CXCR7 knockdown LECs proliferated more than wild-type LECs [25]. Moreover, dermal and cardiac lymphatic beds were disrupted in Cxcr7-null mice and displayed dysmorphic vasculature consistent with hyperplasia [25].…”

“…This difficulty was particularly apparent in Cxcr7-null mice, which exhibited cardiac enlargement and hyperplasia, a phenotype that was not observed in mutant mice of the canonical ligands, SDF-1 and CXCL11 [21,61,62]. However, the cardiac phenotypes closely phenocopied a genetic model of AM overexpression (known as Adm hi/hi mice) which results in gross cardiac hyperplasia during embryogenesis [25,63]. The similarity in cardiac phenotypes and the historical association of AM and CXCR7 sparked curiosity about whether CXCR7 could behave as a decoy receptor for AM.…”

“…Mounting evidence in the literature over the past decade suggests that RDC-1/CXCR7/ACKR3 does indeed associate with adrenomedullin [15,[21][22][23][24]. Although the discovery of RAMP-guided CLR responsiveness to AM overshadowed the role of these other receptors in AM biology, as will be discussed later in this review, recent studies demonstrate that AM-mediated downstream signal is indeed modulated through CXCR7 [25,26]. The identification of a second AM receptor is especially exciting, as it offers another avenue for drug discovery for the treatment of AM-mediated pathologies.…”