Bone morphogenetic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells.
Bone morphogenetic protein (BMP) signals regulate the growth and differentiation of diverse lineages. The association of mutations in the BMP type II receptor (BMPRII) with idiopathic pulmonary arterial hypertension suggests an important role of this receptor in vascular remodeling. Pulmonary artery smooth muscle cells lacking BMPRII can transduce BMP signals using ActRIIa (Activin type II receptor). We investigated whether or not BMP signaling via the two receptors leads to differential effects on vascular smooth muscle cells. BMP4, but not BMP7, inhibited platelet-derived growth factor-activated proliferation in wild-type pulmonary artery smooth muscle cells, whereas neither ligand inhibited the growth of BMPRII-deficient cells. Adenoviral gene transfer of BMPRII enabled BMP4, as well as BMP7, to inhibit proliferation in BMPRII-deficient cells. BMP-mediated growth inhibition was also reconstituted by the BMPRII short isoform, lacking the C-terminal domain present in the long form. BMP4, but not BMP7, induced the expression of osteoblast markers in wild-type cells, whereas neither ligand induced these markers in BMPRII-deficient cells. Overexpression of short or long forms of BMPRII in BMPRII-deficient cells enabled BMP4 and BMP7 to induce osteogenic differentiation. Although signaling via BMPRII or ActRIIa transiently activated SMAD1/5/8, only BMPRII signaling led to persistent SMAD1/5/8 activation and sustained increases in Id1 mRNA and protein expression. Pharmacologic blockade of BMP type I receptor function within 24 h after BMP stimulation abrogated differentiation. These data suggest that sustained BMP pathway activation, such as that mediated by BMPRII, is necessary for growth and differentiation control in vascular smooth muscle.
Yu
Paul B
PB
Cardiovascular Research Center and Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. pbyu@partners.org
Deng
Donna Y
DY
Beppu
Hideyuki
H
Hong
Charles C
CC
Lai
Carol
C
Hoyng
Stefan A
SA
Kawai
Noriko
N
Bloch
Kenneth D
KD
D000818:Animals; D001483:Base Sequence; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D017931:DNA Primers; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011651:Pulmonary Artery / Q000166:cytology*; D034741:RNA, Small Interfering
D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D034741:RNA, Small Interfering; D052006:Bone Morphogenetic Protein Receptors, Type II