Fewer vitamin D receptors in PAH lungs, blood vessel cells: Study
Treatment with calcitriol lowered VDR deficiency, suppressed cell growth
Lung tissue and cells from the blood vessels that pass through the lungs derived from people with pulmonary arterial hypertension (PAH) produced fewer vitamin D receptors (VDRs) than normal, a study shows.
Treating PAH patient-derived blood vessel cells with calcitriol, the active form of vitamin D, reduced VDR deficiency and suppressed the excessive growth of these cells, a hallmark feature of PAH.
“These data reinforce the view that [vitamin D] deficiency may contribute to the [development] of PAH,” the study’s scientists wrote in “Vitamin D receptor and its antiproliferative effect in human pulmonary arterial hypertension,” which was published in Scientific Reports.
In PAH, high blood pressure is caused by the narrowing of the pulmonary arteries, the blood vessels that carry deoxygenated blood from the heart to the lungs to be oxygenated. Arterial narrowing is triggered by the excessive growth of smooth muscle cells (PASMC), the most common cells in blood vessel walls, and endothelial cells (PAEC), which line the inside of blood vessels.
With reduced blood flow through the lungs, PAH symptoms arise due to a lack of oxygen in the blood and include shortness of breath, fatigue, chest pain, dizziness, and fainting. Because high blood pressure in these arteries makes the heart work harder to pump blood, PAH can lead to heart failure.
PAH patients are deficient in vitamin D compared with the general population or people with other cardiovascular diseases, studies show. Such a deficiency has been linked with poor outcomes, including higher pulmonary artery blood pressure, decreased exercise tolerance, and reduced survival.
Calcitriol interacts with the vitamin D receptor, a protein produced in many cell types, including PASMCs and PAECs. When calcitriol binds to VDRs, it enters the nucleus and activates several genes. Along with its well-known function in metabolizing calcium and phosphorus, calcitriol/VDRs also influence cell growth and migration, blood vessel health, and immune responses.
Studyinig VDR production in PAH patients
Here, a research team led by scientists at the Complutense University of Madrid examined the expression, or production, profile of VDR in human lung tissue, PASMCs, and PAECs derived from PAH patients and healthy people to explore the role of VDRs in the pulmonary arteries and PAH.
In human lung tissue, the activity of the gene that encodes VDRs was reduced, as were the levels of VDR protein, in PAH patients compared with healthy people. VDR expression was also reduced in PASMCs from PAH patients, but not in PAECs versus healthy people.
Low levels of lung VDRs are associated with several other lung diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and correlate with worse outcomes.
When treated with calcitriol for 48 hours, VDR expression was significantly increased in PASMCs of PAH patients to levels that were similar to healthy people.
A closer look found that calcitriol suppressed the growth of PASMCs from healthy people and PAH patients in a dose-dependent manner. This effect was more prominent in PAH cells at higher calcitriol doses than healthy people, however.
Using control PASMCs, calcitriol boosted the expression of the KCNK3 gene, which encodes for a potassium channel protein involved in pulmonary circulation, but decreased the expression of BIRC5, a gene that encodes survivin, a protein that blocks programmed cell death. Calcitriol also significantly enhanced the expression of BMP4, which codes for a protein involved in cell growth and migration. The researchers confirmed that calcitriol suppressed PASMC growth partly by modulating the BMP and survivin signaling pathways. Still, calcitriol had no anti-growth effect in PAECs, nor did it act as a vasodilator, a medicine that widens blood vessels.
“PAH patients not only present severe deficit of [vitamin D], but also a reduction in lung VDR,” the scientists wrote. “Calcitriol rescues VDR expression and induces an antiproliferative effect in PASMC.”
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