The Local HIF-2α/EPO Pathway in the Bone Marrow is Associated with Excessive Erythrocytosis and the Increase in Bone Marrow Microvessel Density in Chronic Mountain Sickness

Abstract

. The local HIF-2a/EPO pathway in the bone marrow is associated with excessive erythrocytosis and the increase in bone marrow microvessel density in chronic mountain sickness. High Alt Med Biol. 16:318-330, 2015.-Aim: Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis, and angiogenesis may be involved in the pathogenesis of this disease. The bone marrow niche is the primary site of erythropoiesis and angiogenesis. This study was aimed at investigating the associations of the levels of hypoxia-inducible factors (HIFs), erythropoietin (EPO), and erythropoietin receptor (EPOR), as well as microvessel density (MVD) in the bone marrow with CMS. Results: A total of 34 patients with CMS and 30 control subjects residing in areas at altitudes of 3000-4500 m were recruited for this study. The mRNA and protein expression of HIF-2a and EPO in the bone marrow cells was significantly higher in the CMS patients than in the controls. Moreover, changes in HIF-2a expression in CMS patients were significantly correlated with EPO and hemoglobin levels. In contrast, the expression of mRNA and protein expression of HIF-1a and EPOR did not differ significantly between the CMS and control patients. Increased MVD was observed in the bone marrow of the patients with CMS and it was significantly correlated with hemoglobin. Conclusions: Bone marrow cells of CMS patients may show enhanced activity of the HIF-2a/EPO pathway, and EPO may regulate the erythropoiesis and vasculogenesis through autocrine or/and paracrine mechanisms in the bone marrow niche. The increased MVD in the bone marrow of CMS patients appears to be involved in the pathogenesis of this disease.

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…Sustained hypoxia exposure triggers subsequent vascular pathologic changes such as an increase in blood viscosity and angiogenesis leading to BM degradation [7,8,10,38]. Consistent with previous studies, we observed an increased MVD in the hypoxic experimental groups [6][7][8]. It has been reported that upstream elements of the MMP-9 pathway are involved in the response to hypoxia [21,35,36,38,39].…”

“…It has been reported that upstream elements of the MMP-9 pathway are involved in the response to hypoxia [21,35,36,38,39]. In a previous study, we showed that hypoxia induced the development of MVD in young rats [6]. erefore, in this study, we used adult rats to examine the role of the IL-6/ JAK2/STAT3/MMP-9 pathway in the development of hypoxia-induced MVD.…”

“…MVD was determined using immunofluorescence staining with MMP-9 as a marker for microvessel endothelium, as described previously [6]. Slides were examined at a magnification of ×400 to determine the highest vascular density in the bone marrow.…”

“…e prevalence of CH at high altitude is increased by 10% in Peruvian Andes at an altitude of about 2500 m and by 17.8% in Chinese Han men who migrated to the Qinghai-Tibetan plateau at an altitude of 3700-5000 m [2,4,5]. Previous studies showed that CH arises due to the excessive production of erythrocytes, which increases the blood viscosity causing blood flow retardation leading to exacerbated hypoxic-ischemic injury and eventually angiogenesis and basal membrane (BM) degradation of the blood vessel in tissues [6][7][8][9][10]. In addition, in a previous study, we showed that patients with CH frequently exhibit an erythematic facial color with marked congestion of the mucosa and conjunctiva as a result of the formation of new vessels and that CH is associated with changes in bone marrow MVD [6].…”

“…Previous studies showed that CH arises due to the excessive production of erythrocytes, which increases the blood viscosity causing blood flow retardation leading to exacerbated hypoxic-ischemic injury and eventually angiogenesis and basal membrane (BM) degradation of the blood vessel in tissues [6][7][8][9][10]. In addition, in a previous study, we showed that patients with CH frequently exhibit an erythematic facial color with marked congestion of the mucosa and conjunctiva as a result of the formation of new vessels and that CH is associated with changes in bone marrow MVD [6]. However, the mechanisms underlying the development of CH-induced changes in the microvessels are relatively unknown.…”