Study Probes Role of Vitamin D Receptor in Pulmonary Arterial Hypertension

New research is helping to better characterize the potential links between vitamin D deficiency and pulmonary arterial hypertension (PAH).

The study, which was published in Scientific Reports, centers on expression of vitamin D receptor (VDR) in the lungs, pulmonary artery smooth muscle cells (PASMCs), and endothelial cells of patients with PAH, as well as the apparent antiproliferative effects of the receptor.

Corresponding author Francisco Perez-Vizcaino, Ph.D., of the Complutense University of Madrid, and colleagues, have been examining the role of vitamin D in PAH for many years.

In 2020, the team published findings showing that 70% of patients with PAH had a severe vitamin D deficiency. They also found that vitamin D levels correlated with patient outcomes. For example, patients whose plasma vitamin D levels were above the median of the cohort had a significantly higher chance of survival compared to those with vitamin D levels below the median. The team has also shown that vitamin D deficiency is associated with measures of PAH severity, including functional class and 6-minute walking distance.

While the role of vitamin D deficiency in the PAH has been explored in a number of studies, Perez-Vizcaino and colleagues said VDR expression is an area deserving of more attention. They noted that the receptor is activated by the active form of vitamin D, calcitriol, and that VDR in turn regulates the expression of several target genes. And while VDR is well known for its effects on calcium and phosphorus homeostasis, they said it also has a number of non-calcemic functions.

“These effects have potential relevance in key processes within the cardiovascular and respiratory systems, such as cell proliferation, differentiation and migration, control of vascular tone, immunomodulation and regulation of metabolism among others,” they wrote.

The goal of the new study was to more closely examine the role of VDR in PAH, and in particular its potential antiproliferative effects.

The investigators compared VDR expression in the lungs, PASMCs, and endothelial cells from patients with PAH and from healthy controls.

They found that VDR is expressed in several types of lung cells and in PASMCs, and that it is downregulated in the lungs and PASMCs of people with PAH. Treating PASMCs with calcitriol led to an upregulation of VDR expression in PASMCs and VDR target genes. In addition, they found that calcitriol seemed to have an antiproliferative effect on PAMSCs, which the investigators said appears to be tied to its modulation of survivin and the BMP signalling pathway.

“Altogether the data indicate that calcitriol inhibits PASMC proliferation at least partly by the suppression of survivin,” they wrote, noting that a similar phenomenon was found in certain cancer cells, including prostate and breast cancer.

Perez-Vizcaino and colleagues noted that low levels of VDR have been found in the lungs of patients with several other pulmonary diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

What remains to be seen, though, is the potential therapeutic implications of the research. In an earlier study, published in 2021, Perez-Vizcaino and colleagues used an animal model of PAH to compare rats who were kept on a vitamin D-free diet to rats who initially were depleted of vitamin D but then were given vitamin D supplements. They found that the latter group had improved endothelial function and increased activity in the TASK-1 potassium channels. However, replenishing vitamin D levels did not reduce pulmonary pressure and did not improve pulmonary vascular remodeling and right ventricle hypertrophy. Thus, they said, replenishing vitamin D appeared to have only a “partial” effect on the disease.

For now, the investigators said their new report supports the idea that vitamin D deficiency plays a role in the pathogenesis of PAH, even if the exact role and clinical implications remain unclear.