Bone marrow mononuclear cell angiogenic competency is suppressed by a high-salt diet

Abstract

Autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation is a potential therapy for inducing revascularization in ischemic tissues providing the underlying disease process had not negatively affected BM-MNC function. Previously, we have shown that skeletal muscle angiogenesis induced by electrical stimulation is impaired by a high-salt diet (HSD; 4% NaCl) in Sprague-Dawley (SD) rats. In this study we tested the hypothesis that BM-MNC angiogenic function is impaired by an elevated dietary sodium intake. Following 1 wk on HSD, either vehicle or BM-MNCs derived from SD donor rats on HSD or normal salt diet (NSD; 0.4% NaCl) were injected into male SD rats undergoing hindlimb stimulation. Administration of BM-MNCs (intramuscular or intravenous) from NSD donors, but not HSD donors, restored the angiogenic response in HSD recipients. Angiotensin II (3 ng · kg(-1) · min(-1)) infusion of HSD donor rats restored angiogenic capacity of BM-MNCs, and treatment of NSD donor rats with losartan, an angiotensin II receptor-1 antagonist, inhibited BM-MNC angiogenic competency. HSD BM-MNCs and NSD losartan BM-MNCs exhibited increased apoptosis in vitro following an acute 6-h hypoxic stimulus. HSD BM-MNCs also had increased apoptosis following injection into skeletal muscle. This study suggests that BM-MNC transplantation can restore skeletal muscle angiogenesis and that HSD impairs the angiogenic competency of BM-MNCs due to suppression of the renin-angiotensin system causing increased apoptosis.

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

“…We have previously shown that 7 days of electrical stimulation in vivo produces a robust angiogenic response in rat models that is eliminated by a high salt diet and restored by a low, subpressor dose AngII infusion 7, 21 ; this result was replicated for a control in this study (Figure 1A). In vivo administration of the AT 1 R antagonist Losartan abolished the restorative effect of low dose AngII infusion, whereas Mas1 receptor antagonist A779 had no effect on the ability of low dose AngII infusion to restore angiogenesis.…”

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

“…Reports in ischemia disclosed the involvement of bone marrow (BM)-derived mononuclear cells as contributors for angiogenesis, by being incorporated into neocapillaries and by allowing an increased vessel density [51][52][53]. A study from Nolan et al [54] correlated early stages of tumor development with the differentiation potential of BM-derived EPCs and their incorporation into a subset of tumor neovessels.…”

Bone Marrow Cell Transplantation Time-Dependently Abolishes Efficacy of Granulocyte Colony-Stimulating Factor After Stroke in Hypertensive Rats

“…Nevertheless, adverse effects of BM-derived cells have been described in animal models of diabetes mellitus and arteriosclerosis, 24,25 suggesting a compromised cell graft under translationally relevant conditions of hyperglycemia and hypertension. 26,27 We found almost 30% of the BM MNC being apoptotic before transplantation, a finding that may reflect hypertension-related oxidative stress in the BM. 26,27 In steady state, circulating apoptotic cells were trapped by specialized splenic macrophages in the marginal zone between red and white pulp.…”

“…26,27 We found almost 30% of the BM MNC being apoptotic before transplantation, a finding that may reflect hypertension-related oxidative stress in the BM. 26,27 In steady state, circulating apoptotic cells were trapped by specialized splenic macrophages in the marginal zone between red and white pulp. 28 This endogenous scavenging system carefully downregulates immune-stimulatory functions and helps to maintain self-tolerance.…”