Vitamin D deficiency aggravates monocrotaline-induced pulmonary hypertension in rats

Abstract

Introduction

Pulmonary arterial hypertension (PAH) is a rare, progressive and fatal disease characterized by structural and functional changes in the pulmonary arterioles, leading to increased pulmonary vascular resistance and subsequent right ventricular (RV) failure. Vitamin D deficiency (VDD) is highly prevalent worldwide and has been associated with a poor prognosis in PAH patients. However, the underlying mechanisms remain largely unknown.

Objective

To decipher the impact of VDD on the pathogenesis of experimental pulmonary hypertension (PH) in rats.

Method

Forty-seven male Wistar rats were randomly assigned to either a standard (n = 23) or VDD (n = 24) diet for a period of four weeks. After one week of feeding, monocrotaline (MCT; 40 mg/kg) was intraperitoneally injected to induce PH in 12 standard diet- and 14 VDD diet-fed rats. Three weeks later, hemodynamic assessment was performed by RV catheterization. Pulmonary artery vasoreactivity was characterized ex vivo and lung tissue and blood were harvested for pathobiological evaluation.

Results

Circulating levels of 25(OH) vitamin D were < 10 ng/mL in VDD diet-fed rats, confirming VDD. In MCT rats, VDD worsened PH with increased mean pulmonary artery and RV systolic pressures, and RV hypertrophy. This was associated with increased pulmonary vascular remodeling (characterized by medial thickness) and altered endothelium (in response to acetylcholine) – and smooth muscle (in response to sodium nitroprusside)-dependent relaxation of the pulmonary arteries. At pathobiological level, VDD decreased circulating serum levels of endothelin-1 and pulmonary gene expression (related to expression of the endothelial receptor TIE2) of prepro-endothelin-1 (PPET1/TIE2) and endothelin-converting enzyme (ECE1/TIE2). VDD was also associated with reduced circulating levels of NO (assessed as nitrite levels) and reduced pulmonary endothelial NO-synthase gene expression compared with MCT rats. Histological analysis revealed similar inflammatory infiltrates in rats with MCT-induced PH with or without VDD.

Conclusion

VDD exacerbates MCT-induced PH in rats, through increased vascular remodeling and impaired endothelium- and smooth muscle-dependent relaxation in pulmonary arteries. This highlights the potential role of VDD in the pathogenesis of PAH.