Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH).Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods:We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1.Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phosphoSmad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1 1/2 mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions:We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

The QFT-G and the T-SPOT.TB tests were more sensitive than the TST for diagnosis of latent tuberculosis infection in patients on hemodialysis while offering a comparable level of specificity. This systematic review calls into question the practice of using the TST to screen in this population, especially in patients considered for kidney transplantation.

The bone morphogenetic protein (BMP) type II receptor (BMPR-II) is predominantly expressed on the vascular endothelium in the adult lung. Although mutations in BMPR-II are known to underlie many cases of familial pulmonary arterial hypertension (FPAH), little is known regarding the expression of BMPs and their signalling pathways during normal lung development or the impact of BMPR-II mutations on endothelial cell function. We determined the cellular localization and expression levels of BMP4, BMP receptors, and activation of downstream signalling via phospho-Smad1 in a developmental series of human embryonic and fetal lungs by immunohistochemistry. The expression of BMP4 and BMP receptors was temporally and spatially regulated during lung development. BMPR-II expression correlated with phosphorylation of tissue Smad1 and was highest during the late pseudoglandular and early canalicular stage of lung development, when vasculogenesis is intense. Phospho-Smad1 expression was associated with markers of proliferation in endothelial cells. In vitro studies confirmed that BMPs 2 and 4 induced phosphorylation of Smad1/5 and pulmonary artery endothelial cell (PAEC) migration and proliferation. Adenoviral transfection of PAECs with mutant kinase-deficient BMPR-II, or siRNA knockdown of BMPR-II, inhibited Smad signalling and the proliferative response to BMP4. Our findings support a critical role for BMPs in lung vasculogenesis. Dysfunctional BMP signalling in PAECs during development may lead to abnormal pulmonary vascular development and contribute to the pathogenesis of FPAH.

Background Genome‐wide association studies have shown an association between the single‐nucleotide polymorphism rs17514846 on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. rs17514846 is located in the FES Upstream Region ( FURIN ) gene, which is expressed in vascular endothelial cells (ECs). We investigated whether rs17514846 has an influence on FURIN expression in ECs and whether FURIN affects EC behavior. Methods and Results Quantitative reverse transcription–polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of rs17514846 had higher FURIN expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA ‐protein complex with allele‐specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin‐1 secretion, nuclear factor‐κB activity, vascular cell adhesion molecule‐1, and MCP1 (monocyte chemotactic protein‐1) expression and monocyte‐endothelial adhesion and transmigration. A population‐based study showed an association of the rs17514846 risk allele with higher circulating MCP1 levels and greater carotid intima‐media thickness. Conclusions The coronary artery disease risk variant at the 15q26.1 locus modulates FURIN expression in vascular ECs. FURIN levels in ECs affect monocyte‐endothelial adhesion and migration.