Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells.

Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown.

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family.

Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH.

Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension.

Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH).

Endothelial dysfunction in pulmonary arterial hypertension: loss of cilia length regulation upon cytokine stimulation.

Pulmonary arterial hypertension (PAH) is a syndrome characterized by progressive lung vascular remodelling, endothelial cell (EC) dysfunction, and excessive inflammation. The primary cilium is a sensory antenna that integrates signalling and fine tunes EC responses to various stimuli. Yet, cilia function in the context of deregulated immunity in PAH remains obscure.

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Background: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH).

Methods: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity.

Vascular narrowing in pulmonary arterial hypertension is heterogeneous: rethinking resistance.

In idiopathic pulmonary arterial hypertension (PAH), increased pulmonary vascular resistance is associated with structural narrowing of small (resistance) vessels and increased vascular tone. Current information on pulmonary vascular remodeling is mostly limited to averaged increases in wall thickness, but information on number of vessels affected and internal diameter decreases for vessels of different sizes is limited. Our aim was to quantify numbers of affected vessels and their internal diameter decrease for differently sized vessels in PAH in comparison with non-PAH patients.

Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle.

Background: The effect of a mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension is unknown. Therefore, we investigated RV function in patients who have pulmonary arterial hypertension with and without the BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular tissue.

Methods And Results: In total, 95 patients with idiopathic or familial pulmonary arterial hypertension were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, and 67 patients did not have a BMPR2 mutation.

Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage.

Rationale: Altered pulmonary hemodynamics and fluid flow-induced high shear stress (HSS) are characteristic hallmarks in the pathogenesis of pulmonary arterial hypertension (PAH). However, the contribution of HSS to cellular and vascular alterations in PAH is unclear.

Objectives: We hypothesize that failing shear adaptation is an essential part of the endothelial dysfunction in all forms of PAH and tested whether microvascular endothelial cells (MVECs) or pulmonary arterial endothelial cells (PAECs) from lungs of patients with PAH adapt to HSS and if the shear defect partakes in vascular remodeling in vivo.

SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction.

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology.