Hyperbilirubinemia-induced pro-angiogenic activity of infantile endothelial progenitor cells

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

“…In this context, it has recently been reported that hyperbilirubinemic infants have an increased number of circulating endothelial progenitor cells (cEPC) which also exhibit an increased ability to proliferate, migrate and repair wounds. Indeed, tissues treated with conditioned medium derived from these cells up-regulate the expression of VEGF and IL-10 and reduce TNFα (Jabarpour et al, 2018). The involvement of bilirubin has also been documented in a model of cutaneous wounds, where i.p.…”

“…AngII, angiotensin II; BRT, bilirubin ditaurate; BLVRA, biliverdin reductase; CAD, coronary artery disease; CO, carbon monoxide; CoPPIX, cobalt protoporphyrin IX; CRC, colorectal cancer patients; db/db, diabetic mice; DIO, diet-induced obese; DM, diabetes mellitus; DSS, dextran sodium sulfate; EAE, experimental autoimmune encephalomyelitis; FMD, fasting-mimicking diet; FVB, friend leukemia virus B; GI, gastro-intestinal; GS, Gilbert Syndrome; HFD, high fat diet; IRI, ischemia/reperfusion injury; Ldlr −/− , low-density lipoprotein receptor-deficient mice; MCAO, middle cerebral artery occlusion; MS, multiple sclerosis; OVA, ovalbumin; PMBCs, peripheral blood mononuclear cells; RA, rheumatoid arthritis; SHR, spontaneously hypertensive rat; SJL, Swiss Jim Lambert mice; SLE, systemic lupus erythematosus; SnPP, tin protoporphyrin IX; STS, short-term starvation; STZ, streptozocin; UCB, unconjugated bilirubin; UTG1A1, uridine diphpspho-glucuronosyl transferase 1A1; ZnPP, zinc protoporphyrin IX; WKI, Wistar Kyoto rat. cEPCs 10-20 mg/dl Progenitor endothelial cells induced to proliferate when exposed to 5 mg/dl bilirubin; higher concentrations (up to 20 mg/dl) induce cell death Jabarpour et al, 2018 EA.hy926 0.5-100 µM Exogenous bilirubin increases endothelial antioxidant activity as well as HMOX1-dependent bilirubin generation Ziberna et al, 2016 Commercially EC Not evaluated EC-transfected with HMOX1 release substances that increase healthy adipocytes Peterson et al, 2019 Human and non-human EC HUVECs and H5V cells 0.015 µM < Bf < 0.030 µM UCB, at clinically relevant concentrations, limits over-expression of adhesion molecules and inhibits PMN-endothelial adhesion induced by pro-inflammatory cytokine TNFα, even though UCB itself does not alter expression of these adhesion molecules. Inhibition NF-kappaB transduction pathway Mazzone et al, 2009a,b HAECs and mAECs Not evaluated In HAECs and in primary mAECs from HMOX1 +/+ and HMOX1 −/− , SDF-1 (100-200 ng/ml) favors angiogenesis through the induction of HMOX1 Deshane et al, 2007 (Continued) ( Deshane et al, 2007).…”

Beyond a Measure of Liver Function—Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients

“…Altered function and decreased number of circulating EPCs in patients with CKD have been well established and are recognized as key factors involved in the pathogenesis of endothelial dysfunction and CV complications [87]. A recent study by Jabarpour et al found that circulating EPCs from infants with hyperbilirubinemia exhibited greater proliferative and migratory capacity as compared with EPCs from those with normal bilirubin levels [88]. Additionally, conditioned medium from EPCs isolated from hyperbilirubinemic infants could significantly increase levels of VEGF, IL-10, and p-ERK/ERK in the wound tissues and improve wound healing in the experimental animals [88].…”

“…A recent study by Jabarpour et al found that circulating EPCs from infants with hyperbilirubinemia exhibited greater proliferative and migratory capacity as compared with EPCs from those with normal bilirubin levels [88]. Additionally, conditioned medium from EPCs isolated from hyperbilirubinemic infants could significantly increase levels of VEGF, IL-10, and p-ERK/ERK in the wound tissues and improve wound healing in the experimental animals [88]. Using in vitro functional assays and an in vivo murine hind-limb ischemia model, Ikeda et al further demonstrated that bilirubin may directly promote angiogenesis through activation of Akt/eNOS signaling in endothelial cells [89].…”

Low-Energy Shockwave Treatment Promotes Endothelial Progenitor Cell Homing to the Stenotic Pig Kidney

“…EPCs are circulating bone marrow–derived progenitor cells that contribute to capillary formation and angiogenesis via migration, adhesion, and replacement of damaged endothelial cells. As a result, EPCs can assist in capillary formation, restore blood supply in ischemic tissues, and alleviate endothelial dysfunction 30 , 31 . When circulating EPCs home to sites of vascular injury, they can differentiate into mature endothelial cells to participate in repair, or release proangiogenic mediators.…”