Erythropoietin recapitulates ultrasound-assessed hemodynamic and morphological features of hypoxia-induced pulmonary hypertension in mice

Abstract

Introduction

Pulmonary hypertension is characterized by increased pulmonary vascular resistances leading to right ventricular failure. Chronic hypoxia is a risk factor for PH. End-stage renal disease patients with chronic haemodialysis have increased risk of PH. Most of these are treated with erythropoietin (EPO) because of anaemia. Involvement EPO as causative of PH in controversial.

Objective

We investigated if an EPO treatment could reproduce hemodynamic and morphologic features of hypoxia-induced PH and whether endothelial progenitor cells mobilized in PH due to hypoxia, could be involved in EPO-induced PH.

Method

The first group of mice was treated with EPO for 2 and 4 weeks and the 2nd group of hypoxia (10%) was exposed during 2 and 4 weeks. Blood analysis, heart and valves remodeling and function were assessed by high frequency echocardiography (Vevo3100 from Visual sonics) using a linear MS440 and MS500 probe. Isovolumetric relaxation and contraction time were recorded with a pulsed-Doppler window placed at the tip of the leaflets valves and right ventricle strain was also evaluated. Blood pressure and heart rate were recorded. Right ventricular pressure, heart and lung histology and blood circulating endothelial progenitor cells were assessed after 2 weeks.

Results

The EPO treatment for 2 weeks and 4 weeks and hypoxia induce PH with an important increase in pulmonary and right ventricular pressure and RV/LV + septum size attested by pulmonary and peripheral vein pressure increases compared to normoxia animals. Similarly, the treatment with EPO or hypoxia in mice significantly alters the inferior vena cava (IVC) pulsatility index with a decrease in inspiratory fractional shortening. EPO and hypoxia groups show right ventricle hypertrophy as attested by an increased in RV/LV + septum weight ratio and pulmonary artery remodeling increased pulmonary wall vessel thickening of vessels with a diameter below 3–4 μm (pre-acinar and intra-acinar pulmonary vessels) with an elastic fibrosis of alveolar vessels wall. EPO provoked an increase in the blood mobilization of endothelial progenitor cells at a similar extent than hypoxia.

Conclusion

EPO recapitulates hemodynamic features of hypoxia-induced pulmonary hypertension in mice when hematocrit is increased over the physiological range. Nevertheless a pharmacological effect not linked to hematopoiesis is discussed.