Adrenomedullin augments the angiogenic potential of late outgrowth endothelial progenitor cells

Abstract

The therapeutic utility of endothelial progenitor cells (EPCs) in cardiovascular disease is potentially hampered by their low numbers in the circulation, impaired functional activity, and inhibitory factors in the recipient. These obstacles can possibly be circumvented by the use of proangiogenic cytokines and peptides. We sought to examine the effect of the endogenous vasoactive peptide adrenomedullin (AM) on the angiogenic potential of late outgrowth EPCs and their release of proangiogenic and proinflammatory cytokines/chemokines. Human peripheral blood mononuclear cells were cultured until the appearance of typical late outgrowth EPC colonies. The effect of AM on EPC proliferation was assessed using a colorimetric MTS proliferation assay while differentiation and formation of tubular structures in an EPC/fibroblast coculture or matrigel assay was used to assess the angiogenic potential of the cells. Finally, the release and mRNA transcripts of cytokines/chemokines were quantified in stimulated vs. nonstimulated EPCs using real-time PCR and a bead-based multiplex assay. The cultured EPCs possessed an endothelial phenotype and expressed the AM receptor (calcitonin receptor-like receptor/receptor activity modifying protein-2). AM stimulation induced proliferation of EPCs compared with controls (P < 0.05). Furthermore, AM produced a 36% and 80% increase in the formation of tubular networks in the EPC/fibroblast coculture and matrigel assay, respectively (P < 0.05). These effects seemed to be mediated through the phosphatidylinositol 3-kinase/Akt signaling pathway. AM did not seem to significantly influence the release or production of IL-6, IL-8, VEGF, stromal cell-derived factor 1, or the expression of CXCR-4 or VEGF receptor 2. In conclusion, adrenomedullin augmented the growth and angiogenic properties of late outgrowth EPCs, but did not influence their paracrine properties.

Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells

“…MIP-1α and MIP-1β are chemokines that can activate granulocytes and initiate an inflammatory response. Several other investigators have suggested that MIP-1 chemokines may be an important mediator of hyperoxia-induced acute [23] and chronic [19, 39] lung injury in mice. Thus, our result in human cells signify the beneficial anti-inflammatory role of the AM in hyperoxia-induced lung disorders in humans.…”

“…al demonstrated that a constitutively active form of Akt is sufficient to protect adult mice from hyperoxic lung injury [22]. Interestingly, AM is shown to regulate prosurvival properties of endothelial progenitor [23] and cardiac [24] cells via Akt activation.…”

Adrenomedullin as a Growth and Cell Fate Regulatory Factor for Adult Neural Stem Cells

“…Hermansen et al [134] confirmed that cultured EPCs possess an endothelial phenotype and express the AM receptor complex CLR/RAMP2. AM stimulation induced proliferation of EPCs and increased the formation of tubular networks in the EPC/fibroblast coculture and matrigel assays.…”

The Renal Protective Effect of Jiangya Tongluo Formula, through Regulation of Adrenomedullin and Angiotensin II, in Rats with Hypertensive Nephrosclerosis

“…Traditional Chinese medicine (TCM) has been used since a long time and positive treatment effects have been observed in hypertensive nephrosclerosis [27, 28]. JYTL formula used in this study is composed of Nacre, Cassia occidentalis, Safflower, Salvia miltiorrhiza, and Chrysanthemum .…”