Bone Morphogenetic Protein (BMP) Type II Receptor Is Required for BMP-mediated Growth Arrest and Differentiation in Pulmonary Artery Smooth Muscle Cells

Abstract

Bone morphogenetic proteins (BMPs) 2 are members of the TGF-␤ family that play essential roles in early embryonic patterning, gastrulation, and organogenesis as well as in the remodeling of mature tissues (1). BMP signals are involved in the commitment of vascular precursor cells in vasculogenesis and regulate the growth, differentiation, and turnover of vascular cell populations (2-4). There is increasing evidence that BMP signals contribute to vascular calcific disease of the intima and tunica media (5). Further underscoring the importance of BMP signaling in vascular tissues, defects in the BMP signaling apparatus have been linked to two genetic vascular syndromes, hereditary hemorrhagic telangectasia syndrome and idiopathic pulmonary arterial hypertension (4). In idiopathic pulmonary arterial hypertension, diverse loss-of-function mutations in the canonical BMP type II receptor (BMPRII) are associated with the majority of familial and a subset of sporadic cases (6 -9). Advanced idiopathic pulmonary arterial hypertension is marked by an obstructive and proliferative vasculopathy involving endothelial and myofibroblast lineages (10). Although it has been suggested that defective BMP-mediated regulation of cell differentiation and turnover could contribute to abnormal vascular remodeling, the precise contribution of BMPRII to these functions is incompletely understood.Signaling by BMP ligands is accomplished by at least three type II receptors, BMPRII, ActRIIa, and ActRIIb, and three type I receptors, ALK2, ALK3, and ALK6 (11)(12)(13)(14)(15)(16)(17)(18)(19). At least 25 different BMP ligands can facilitate the assembly of type II and type I receptor heteromers to cause phosphorylation and activation of type I receptor kinases by constitutively active type II receptor kinases. Activated type I receptors phosphorylate BMP-responsive SMAD (BR-SMAD) intracellular effectors (SMAD1, -5, and -8). Downstream effects of BR-SMAD activation are mediated in part by the transcription of the dominant negative bHLH Inhibitor of differentiation (Id) proteins, as well as by

TGF-β signaling in vascular biology and dysfunction

“…Mutations in BMPRII also can deregulate Id gene expression [103]. BMPRII signaling was found to be essential for BMP-mediated regulation of vascular SMC growth and differentiation [104]. Clinical trials with prostanoids, endothelin antagonists and phosphodiesterase inhibitors have shown promising results in the treatment of PAH.…”

Epigenetic regulation of pulmonary arterial hypertension

“…53,54 Evidence is also emerging that loss of BMPR2 function in smooth muscle, including BMPR2 gene mutation and expression reduction, is sufficient to produce PAH. 53,55,56 Furthermore, loss of BMPR2 signaling in endothelium could induce the formation of plexiform lesions. 53 Morrell et al 57 found that BMP can inhibit proliferation of smooth muscle cells originating from normal pulmonary arteries, but fails to suppress the proliferation of those from primary pulmonary hypertension.…”

“…10,56 The promoter of Id1 gene contains BMP-responsive element, which consists of Smad-binding elements and a GC-rich region. 58 In addition to hypoxia-inducible factor-1a, HDAC recruitment in the Id1 promoter is also involved in hypoxia-induced PAH.…”

Pulmonary Hypertension: Endothelial Cell Function

“…BMPRII signaling is essential for BMP-mediated regulation of vascular smooth muscle cell (SMC) growth and differentiation, and it also protects EC from apoptosis (Yu 2008, TeichertKuliszewska 2006. In some cell systems, persistent activation of PY-STAT3 leads to a reduction in the BMPRII protein expression, and BMP2 induces apoptosis by inhibiting PY-STAT3 activation and by down-regulating Bcl-xL, a downstream mediator of PY-STAT3 (Brock 2009, Kawamura 2000.…”