Novel Advances in Modifying BMPR2 Signaling in PAH.

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling.

Effect of bone morphogenetic protein-6 on macrophages.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-beta superfamily which regulates bone formation, haematopoiesis and development. While TGF-beta is known to be a negative regulator of the immune system, the effect of BMPs on the immune system is largely unknown. Herein, the effect of BMP-6 on the innate immune system was investigated using the murine macrophage cell line RAW 264.7. BMP-6 altered cellular morphology, inhibited cellular proliferation, increased the fraction of subG(1) phase cells, and decreased the fraction of cells in the S and G(2)M phases, without changing the percentage of apoptotic cells. In addition, BMP-6 induced expression of pro-inflammatory inducible nitric oxide synthase (iNOS) and the cytokine tumour necrosis factor (TNF)-alpha. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated the expression of all three known type II BMP receptors [BMP-RII, activin (Act)-RIIA and Act-RIIB] and two of the three known type I receptors [activin receptor-like kinase 2 (ALK2) and ALK3]. Over-expression as well as knock-down studies using short hairpin RNA (shRNA) demonstrated that BMP-RII, ALK2 and ALK3 are the functional BMP-6 receptors in macrophages. Finally, the effect of BMP-6 was confirmed in murine peritoneal macrophages and the THP-1 human monocyte cell line. Taken together, these results demonstrate that BMP-6 regulates the proliferation and gene expression profile of macrophages.

Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors.

Vascular smooth muscle cells (VSMCs), unlike other muscle cells, do not terminally differentiate. In response to injury, VSMCs change phenotype, proliferate, and migrate as part of the repair process. Dysregulation of this plasticity program contributes to the pathogenesis of several vascular disorders, such as atherosclerosis, restenosis, and hypertension. The discovery of mutations in the gene encoding BMPRII, the type II subunit of the receptor for bone morphogenetic proteins (BMPs), in patients with pulmonary arterial hypertension (PAH) provided an indication that BMP signaling may affect the homeostasis of VSMCs and their phenotype modulation. Here we report that BMP signaling potently induces SMC-specific genes in pluripotent cells and prevents dedifferentiation of arterial SMCs. The BMP-induced phenotype switch requires intact RhoA/ROCK signaling but is not blocked by inhibitors of the TGFbeta and PI3K/Akt pathways. Furthermore, nuclear localization and recruitment of the myocardin-related transcription factors (MRTF-A and MRTF-B) to a smooth muscle alpha-actin promoter is observed in response to BMP treatment. Thus, BMP signaling modulates VSMC phenotype via cross-talk with the RhoA/MRTFs pathway, and may contribute to the development of the pathological characteristics observed in patients with PAH and other obliterative vascular diseases.