Bone marrow mononuclear cells induce beneficial remodeling and reduce diastolic dysfunction in the left ventricle of hypertensive SS/MCWi rats

Abstract

Little is known about the effectiveness of BMMNC therapy in hypertensive heart disease. In the current study, we show that delivery of BMMNCs from hypertension protected SS-13 BN /MCWi donor rats, but not BMMNC from hypertension susceptible SS/MCWi donor rats, resulted in 57.2 and 83.4% reductions in perivascular and interstitial fibrosis, respectively, as well as a 60% increase in capillary-to-myocyte count in the left ventricles (LV) of hypertensive SS/MCWi recipients. These histological changes were associated with improvements in LV compliance and relaxation (103 and 46.4% improvements, respectively). Furthermore, improved diastolic function in hypertensive SS/MCWi rats receiving SS-13 BN /MCWi derived BMMNCs was associated with lower clinical indicators of heart failure, including reductions in end diastolic pressure (65%) and serum brain natriuretic peptide levels (49.9%) with no improvements observed in rats receiving SS/MCWi BMMNCs. SS/MCWi rats had a lower percentage of endothelial progenitor cells in their bone marrow relative to SS-13 BN /MCWi rats. These results suggest that administration of BMMNCs can prevent or reverse pathological remodeling in hypertensive heart disease, which contributes to ameliorating diastolic dysfunction and associated symptomology. Furthermore, the health and hypertension susceptibility of the BMMNC donor are important factors influencing therapeutic efficacy, possibly via differences in the cellular composition of bone marrow.

Vascular endothelial growth factor-A signaling in bone marrow-derived endothelial progenitor cells exposed to hypoxic stress

“…After day 3 of culture, nonadherent cells were removed and new media were provided, with subsequent medium changes every 3 days until day 10 -14 or when plated cells reached ϳ60% confluence. Previous characterization of this BM-EPC population under the same isolation and growth conditions by our laboratory (data not shown) indicated that ϳ90% of the cells are positive for a panel of markers including VEGFR2, CD34, CD133, cKIT, and Ac-LDL (16,50). Additionally, throughout this study, we utilize conditions of standard cell culture normoxia (20% O 2) and hypoxia (2% O2) shown to regulate VEGFRs at the cell surface (39), which can vary in vivo depending on the subset of vessels.…”

“…BM-EPCs were isolated from Sprague-Dawley (SD) rat (Harlan) hind limbs according to these approved protocols. Bone marrow isolation (50), BM-EPC culture in MCDB131 basal media (US Biologicals) plus 10% FBS (GIBCO by Invitrogen) and EGM-2 supplement packs (Lonza), and phenotypic verification were performed as previously described (16,50). Using a set of accepted growth conditions (20), we plated approximately five million isolated primary bone marrow mononuclear cells (16) per bovine fibronectin-coated (10 g/ml) 100 mm plate.…”

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

“…SD donor rats were placed on a normal-salt diet (NSD; 0.4% NaCl Dyets) or a high-salt diet (HSD; 4% NaCl Dyets) for 7 days before cell isolation. Donor rats were killed with an overdose of beuthanasia, and their BM-MNCs were harvested as previously described (14,42). Briefly, bone marrow was harvested from the tibias and femurs by flushing with MCDB131 (E3000-01B; US Biologicals) with 5% heat-inactivated fetal bovine serum (FBS; GIBCO by Invitrogen).…”

Genome-wide epigenetic and proteomic analysis reveals altered Notch signaling in EPC dysfunction

“…EPC transplantation also increased microvessel density and decreased fibrosis in cardiac tissue in a salt‐sensitive hypertensive rat model, by increasing blood flow and an improving diastolic function (Parker et al. ). Under some experimental conditions EPCs can incorporate into blood vessels (Yeh et al.…”