Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension.
BACKGROUND
Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. PAH is now further subclassified as idiopathic PAH, familial PAH, and associated PAH varieties. Heterozygous mutations in BMPR2 can be detected in 50% to 70% of patients with familial PAH and 10% to 40% of patients with idiopathic PAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH.


RESULTS
The Bmpr2 gene was deleted in pulmonary endothelial cells using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure were observed in mice with heterozygous (21.7 to 44.1 mm Hg; median, 23.7 mm Hg) and homozygous (20.7 to 56.3 mm Hg; median, 27 mm Hg) conditional deletion of Bmpr2 in pulmonary endothelial cells compared with control mice (19.9 to 26.7 mm Hg; median, 23 mm Hg) at 2 to 7 months of age. A subset of mice with right ventricular systolic pressure >30 mm Hg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these mice with high right ventricular systolic pressure, the expression of proteins involved in the pathogenesis of PAH such as serotonin transporter and tenascin-C was elevated in distal arteries and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis.


CONCLUSIONS
Conditional heterozygous or homozygous Bmpr2 deletion in pulmonary endothelial cells predisposes mice to develop PAH.
Hong
Kwon-Ho
KH
Department of Physiology and Functional Genomics, Shands Cancer Center, University of Florida College of Medicine, Gainesville, USA.
Lee
Young Jae
YJ
Lee
Eunji
E
Park
Sung Ok
SO
Han
Chul
C
Beppu
Hideyuki
H
Li
En
E
Raizada
Mohan K
MK
Bloch
Kenneth D
KD
Oh
S Paul
SP
D000199:Actins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D008168:Lung / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology
D000199:Actins; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II