Increase in Vascular Permeability and Vasodilation Are Critical for Proangiogenic Effects of Stem Cell Therapy

Abstract

Background-Proangiogenic cell therapy based on administration of bone marrow-derived mononuclear cells (BMCs) or endothelial progenitor cells (EPCs) is now under investigation in humans for the treatment of ischemic diseases. However, mechanisms leading to the beneficial effects of BMCs and EPCs remain unclear. Methods and Results-BMC-and CD34ϩ -derived progenitor cells interacted with ischemic femoral arteries through SDF-1 and CXCR4 signaling and released nitric oxide (NO) via an endothelial nitric oxide synthase (eNOS)-dependent pathway. BMC-induced NO production promoted a marked vasodilation and disrupted vascular endothelial-cadherin/ ␤-catenin complexes, leading to increased vascular permeability. NO-dependent vasodilation and hyperpermeability were critical for BMC infiltration in ischemic tissues and their proangiogenic potential in a model of hindlimb ischemia in mice. Conclusions-Our results propose a new concept that proangiogenic progenitor cell activity does not rely only on their ability to differentiate into endothelial cells but rather on their capacity to modulate the function of preexisting vessels.

Hypertension Impairs Postnatal Vasculogenesis

“…Laser-doppler perfusion imaging was also used to assess in vivo tissue perfusion in the paw, as previously described. 3,20 …”

“…3,4 Alternatively, 5 mL of blood was collected in EDTA-containing tubes. After centrifugation on a Ficoll gradient and red cell lysis, circulating blood mononuclear cells were then analyzed in flow analysis cytometry system (FACS).…”

“…In addition, circulating progenitor cells may deliver angiogenic growth factors to pathological tissues and contribute to neovascularization and tissue/vessel remodeling by paracrine effects. 2,3 In most clinical settings, however, these natural adaptive responses to a compromised perfusion are insufficient to block the progression of ischemic diseases. Hence, certain cardiovascular risk factors including diabetes, aging, and hypercholesterolemia adversely affect postnatal vasculogenesis and revascularization in animals models of limb ischemia.…”

Working hypothesis to redefine endothelial progenitor cells

“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Sprouted endothelium may line the vessel lumen while other cells support vessel formation through secretion of cytokines and modification of the extracellular space. [40][41][42][43][44][45] Although each cell type appears to be fundamentally different, all cell types involved in postnatal vasculogenesis have been lumped into the single term 'EPC'. Here, we attempt to clarify study results by closely examining and comparing the methods used to define different cell populations and in the end, propose some unifying working hypotheses.…”

Thérapies cellulaires pro-angiogéniques dans le traitement des pathologies ischémiques

“…Ainsi, le rôle premier des progéniteurs pourrait être de libérer des facteurs angiogéniques et artériogéniques contribuant ainsi à la régénération vasculaire par des effets paracrines. Par leur capacité à réguler le tonus vasculaire et à induire une vasodilatation via un mécanisme dépendant de la voie eNOS (endothelial nitric oxide synthase), les cellules progénitrices sont également susceptibles de participer à l'amélioration de la perfusion tissulaire dans le territoire ischémié [23]. Enfin, les cellules progé-nitrices, par leur sécrétion de cytokines anti-inflammatoires comme l'interleukine-10, peuvent améliorer la fonction cardiaque après un infarctus du myocarde [24].…”