J Hum Hypertens. 2014 Sep;28(9):543-50. doi: 10.1038/jhh.2014.7.

Circulating progenitor cells in hypertensive patients with different degrees of cardiovascular involvement.


Mandraffino G1, Imbalzano E1, Sardo MA1, D’Ascola A2, Mamone F1, Lo Gullo A1, Alibrandi A3, Loddo S2, Mormina E4, David A5, Saitta A1.
  • 1Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
  • 2Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Messina, Italy.
  • 3Department of Statistics, University of Messina, Messina, Italy.
  • 4Department of Biomedical Sciences and of Morphologic and Functional Images, University of Messina, Messina, Italy.
  • 5Department of Neuroscience and Anesthesiology, University of Messina, Messina, Italy.



We investigated whether different degrees of hypertension-related cardiovascular involvement are associated with changes in circulating proangiogenic hematopoietic cell (PHC) numbers and/or phenotypes and/or in the PHC redox system in hypertensive individuals with isolated arterial stiffening (AS) hypertensives or with both carotid intima-media thickening and left ventricular hypertrophy (LVH) hypertensives. We also evaluated microRNA (miRs) 221 and 222 (miRs221/222) expression in CD34+ cells, the relationship between these miRs and cell number and reactive oxygen species (ROS) levels, and the expression of manganese superoxide dismutase (MnSOD), catalase (CAT) glutathione peroxidase type-1 (GPx-1) and gp91phox-containing nicotinamide-adenine-dinucleotide-phosphate-oxidase (NOX2). Proangiogenic hematopoietic cells (PHCs) from hypertensive patients and controls were isolated by flow cytometry. PHCs were higher in hypertensives than in controls but were lower in LVH than in AS hypertensives. In CD34+ cells from AS hypertensives, NOX2, MnSOD, CAT and GPx-1 were overexpressed; ROS, miRs and NOX2 were also increased and were associated with cell number. In LVH, we found an imbalance in the cell redox system; MnSOD showed the highest values, whereas CAT and GPx-1 were lower than in AS hypertensives. Intracellular ROS, miRs and NOX2 were higher and inversely associated with cell number. In AS hypertensives, the redox balance may sustain the increase in PHCs; by contrast, in hypertensives with more advanced lesions, redox imbalance may result in increased oxidative stress and cell reduction.

PMID: 24553637



In this study, the number and the main immunophenotypes of circulating progenitor cells (CPCs) were evaluated in 94 hypertensive patients with subclinical (53 patients) and more advanced target organ involvement (41 patients), and also in 64 normotensive control subjects; subclinical hypertension-related vascular organ damage was identified by the presence of arterial stiffening (AS), while increased carotid intima-media thickness (cIMT) and left ventricular hypertrophy (LVH) were considered as more advanced hypertension-related organ damage. In circulating progenitors, we evaluated the oxido-reductive status, and also the expression of two specific miRs (miR 221 and miR222) found to be associated to the modulation of vascular endothelial function, health and impairment. The aim of the present study was to investigate whether the development of organ damage in hypertensive patients was associated with changes in CPC pattern, cell enzymatic arrangement and whether these changes could explain the modification in the number of circulating progenitors in AS and LVH hypertensives. It is to date accepted, in fact, that CPCs, including the sub-population represented by endothelial progenitor cells (EPCs), play an important role in maintaining an adequate turnover of healthy and damaged endothelium, as well as in angiogenetic processes. Consistently, low CPC number has been repeatedly associated with several conditions of increased cardiovascular risk and vascular damage; consequently, their number is considered as an independent predictor of CV events. Although the question of which cell phenotype better identifies the “true” circulating EPC remains unsolved, it was remarked that several different circulating progenitors may contribute to sustain the regenerative/reparative potential; these cell types, able to work as support cells, were also defined as proangiogenic hematopoietic cells (PHCs).

AS, cIMT and LV indexed mass were evaluated by ultrasonography. Circulating progenitors were identified and counted by flow cytometry. We studied five different cell phenotypes: CD34+cells, CD133+cells, CD34+/KDR+cells, CD133+/KDR+ cells, and double positive CD34+/CD133+cells. Molecular analyses were performed on CD34+ cells: we evaluated the expression of MnSOD, GPx-1, CAT, NOX2 and miRs, and intracellular ROS levels. We have chosen to limit the investigation to CD34+ cell phenotype, since, apart from this subset, the other main PHC phenotypes are relatively rare in peripheral blood.



Figure 1.


The results about PHC counts are graphically reported in Figure 1. ROS levels were increased in LVH with respect to AS hypertensives and controls. miR221/222 expression (n-fold) was higher in hypertensives than in controls, more markedly in LVH hypertensives. CRP, fibrinogen, ROS and miRs levels appeared to gradually increase from controls to LVH hypertensives (Figure 2).

We found that hypertensive patients have an increased circulating PHC number, although patients with more advances target organ involvement presented with lower count with respect to those with earlier vascular damage; moreover, different PHC phenotypes behave differently in AS or in LVH hypertensives with respect to healthy subjects. The oxido-reductive status in CD34+ cells appears to be critically altered in the presence of earlier or more advanced hypertension-related organ damage, as was the expression of miR221/222.

This work could provide new insights about the modulation of vascular endothelial homeostasis and the development and the progression of hypertension-related organ damage.



Figure 2.





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