Sympathetic Nervous System Regulates Bone Marrow–Derived Cell Egress Through Endothelial Nitric Oxide Synthase Activation

Abstract

Objective-Catecholamines have been shown to control bone marrow (BM)-derived cell egress, yet the cellular and molecular mechanisms involved in this effect and their subsequent participation to postischemic vessel growth are poorly understood. Methods and Results-Tyrosine hydroxylase mRNA levels, as well as dopamine (DA) and norepinephrine (NE) contents, were increased in the ischemic BM of mice with right femoral artery ligation. Angiographic score, capillary density, and arteriole number were markedly increased by treatments with DA (IP, 50 mg/kg, 5 days) or NE (IP, 2.5 mg/kg, 5 days). Using chimeric mice lethally irradiated and transplanted with BM-derived cells from green fluorescent protein mice, we showed that DA and NE enhanced by 70% (PϽ0.01) and 62% (PϽ0.001), respectively, the number of green fluorescent protein-positive BM-derived cells in ischemic tissue and promoted their ability to differentiate into cells with endothelial and inflammatory phenotypes. Similarly, both DA and NE increased the in vitro differentiation of cultured BM-derived cells into cells with endothelial phenotype. This increase was blunted by the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester. DA and NE also upregulated the number of CD45-positive cells in blood 3 days after ischemia and that of macrophages in ischemic tissue 21 days after ischemia. Of interest, DA and NE increased BM endothelial nitric oxide synthase (eNOS) mRNA levels and were unable to promote BM-derived cell mobilization in chimeric eNOS-deficient mice lethally irradiated and transplanted with BM-derived cells from wild-type animals. Furthermore, administration of a ␤2 adrenergic agonist (clenbuterol, IP, 2 mg/kg, 5 days) and that of a dopaminergic D1/D5 receptor agonist (SKF-38393, IP, 2.5 mg/kg, 5 days) also enhanced BM-derived cell mobilization and subsequently postischemic vessel growth. Key Words: angiogenesis Ⅲ catecholamines Ⅲ ischemia Ⅲ nitric oxide Ⅲ nitric oxide synthase M obilization and recruitment of bone marrow (BM)-derived cells are of paramount importance and occupy a predominant hierarchical role in the orchestration of tissue remodeling after ischemia. Progenitor cells maintenance and mobilization in the BM are controlled by various cytokines, including colony-stimulating factors and angiogenic cytokines 1 and involve activation of proteinases, such as elastase, cathepsin G, and the matrix metalloproteinases (MMPs). Among them, MMP-9 upregulation results in the release of soluble Kit-ligand expressed by stromal cells and in the activation of BM progenitor cells motility and mobilization. 2 Furthermore, MMP-9 was demonstrated to be essential for vascular endothelial growth factor (VEGF)-induced, CXCL12-induced, and placenta growth factor-induced progenitor cell mobilization. It is also known that BM-derived endothelial nitric oxide synthase (eNOS) is a substantial component of the stem cell niche and is required for the mobilization of BM-derived progenitor cells [3][4][5] Of interest, eNOS-deficient mice show a profoundly re...

Norepinephrine Stimulates Mobilization of Endothelial Progenitor Cells after Limb Ischemia

“…It has been reported that limb ischemia increase tyrosine hydroxylase mRNA levels and catecholamines synthesis within BM. [14] In the present study, we found that co-treatment of α adrenoceptor blocker and β 2 adrenoceptor blocker attenuated the elevation of EPCs. These results were consistent with previous studies in which in vivo adenoviral-mediated gene transfer of the human β2 adrenergic receptor improved hindlimb perfusion and capillary density [15].…”

“…[8] It is now well established that BM and secondary lymphoid tissues are innervated by noradrenergic sympathetic nerve fibers, which release catecholamines from the sympathetic nerve terminals. Recent evidence suggests that catecholamines are also able to control BM derived cells mobilization [9]. Administration of a β2 adrenergic agonist enhances mobilization of progenitor cells in both control and norepinephrine (NE)-deficient mice.…”

Sympathetic predominance is associated with impaired endothelial progenitor cells and tunneling nanotubes in controlled-hypertensive patients

“…Studies in rodents showed that the sympathetic nervous system plays an essential role in EPC mobilization from the bone marrow (22) and that catecholamines are involved in the modulation of postischemic revascularization (31), suggesting that autonomic dysregulation can impair vascular endothelial repair. In humans, the relation between sympathetic activation and EPC egress from the bone marrow was indirectly suggested by reports showing a negative relation between the number of circulating EPC and both psychosocial stressors (13) and depression scores (8), which are known to be associated with autonomic derangements.…”

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity

“…Catecholamines have been previously shown to contribute to collateral artery growth and arteriogenesis in hindlimb ischemia in mice 54,55 ; this was attributed to trophic effects of adrenergic signaling on arterial smooth muscle cells and mobilization of bone marrow-derived hematopoietic cells that contribute to hindlimb revascularization. Our data extend these findings by revealing potential direct effects of catecholamines on arterial endothelial cells themselves.…”