Endogenous catecholamine stimulation of adrenergic receptors contributes to artery growth and remodeling in pathological and adaptive physiological settings. Recently, it has been shown that enforced stem/progenitor cells egress from bone marrow (BM) niches depends critically on the nervous system. In particular, pharmacological or genetic ablation of adrenergic neurotransmission indicates that noradrenalin (NA) signaling controls bone SDF-1 downregulation, and hematopoietic stem cells mobilization. We hypothesized that catecholamines may control vascular progenitor cells mobilization from bone marrow and subsequently trigger post-ischemic neovascularization.

Ischemia was induced by right femoral artery ligation in C57Bl6 mice (n=7 per group) treated with or without 6-hydroxydopamin (6-OHDA, 100mg/kg, i.p., 2 days), clenbuterol (2mg/kg, i.p., 5 days), dopamine (DA, 50mg/kg, i.p., 5 days), NA (2.5mg/kg, i.p., 5 days) and eticlopride (10mg/kg, i.p., 5 days). Sympathectomy induced by 6-OHDA led to a decrease in foot perfusion, angiographic score and capillary density by 41.4 % (p<0.001), 20.2 % (p<0.01) and 21.6 % (p<0.05) respectively, compared to controls, 21 days after ischemia. In contrast, administration of DA and NA increased angiographic score by 57.4 % (p=0.05) and 80.3 % (p<0.05), respectively and raised capillary density by around 15 % (p<0.01). Treatment with the β2-receptor agonist, clenbuterol, increased vessel and capillary densities by 30 % and 13 %, respectively (p<0.01 versus untreated control). Injection of eticlopride, a specific DA D2 receptor antagonist, also raised vessel density compared to controls. We next assessed the mobilization of stem/progenitor cells from bone marrow and their recruitment to ischemic tissue using chimeric mice lethally irradiated and transplanted with BM mononuclear cells isolated from GFP mice. Three days after ischemia, the number of GFP/ BS-1 lectin positive cells was reduced by 53.7 % (p<0.05) in the ischemic muscle of mice treated with 6-OHDA compared with controls. In contrast, clenbuterol increased by 46.4 % (p<0.05) the number of double positive cells suggesting that β2-receptor activation mediates BM stem cells mobilization and incorporation into vascular structure.

Therefore, activation of the β2-receptor promotes postnatal vessel growth in response to ischemia. This effect is likely mediated by activation of stem/progenitor cells migration out of the bone marrow.