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ALK1 belongs to the type I receptor family for transforming growth factor-␤ family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-␤1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-␤ type I receptor, ALK5, regulate angiogenesis by controlling TGF-␤ signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet IntroductionHereditary hemorrhagic telangiectasia (HHT) is an autosomaldominant vascular disorder characterized by recurrent nosebleeds, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in the brain, lungs, liver, and gastrointestinal tract. 1,2 It has been shown that heterozygous mutations in ENDOGLIN (ENG) and Activin receptor-like kinase 1 (ALK1) cause HHT1 and HHT2, respectively. 2-4 Both of these genes are expressed predominantly in endothelial cells. 5,6 Because ENG and ALK1 are transforming growth factor-␤ (TGF-␤) type III and type I receptors, respectively, it has been postulated that HHT is caused by impaired signaling of a common TGF-␤ family ligand that interacts with these 2 receptors. Recent finding of mutations in the common downstream mediator of TGF-␤ family signals, SMAD4, in a subset of HHT patients also support this hypothesis. 7 Despite the identification of these genes responsible for HHT, the underlying mechanisms for the pathogenesis of HHT remain obscure. One of the chief contributing factors underlying this obscurity is the complexity of the transduction pathway of ENG, ALK1, and SMAD4. The TGF-␤ superfamily consists of more than 40 ligands that can be classified into several subfamilies, including TGF-␤, Activin, and bone morphogenetic protein (BMP). 8 TGF-␤ family cytokines exert their effects by binding to heteromeric complexes of 2 types of transmembrane serine/threonine kinase receptors. 9 The type II receptors function primarily as the binding receptors. On binding their ligand(s), type II receptors associate with and phosphorylate the type I receptors, which in turn activate downstream SMAD proteins. Each TGF-␤ ligand interacts with one or more type II and type I receptors, but TGFBR2 is the only type II receptor that has been shown to interact with TGF-␤ subfamily ligands (TGF-␤1, -␤2, and -␤3).ENG can interact with multiple TGF-␤ family members, such as TGF-␤1/␤3, Activin-A, BMP2, and BMP7, in the presence of a suitable ligand-binding type II...

Background Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse etiologies. PAH is now further subclassified as idiopathic (IPAH), familial (FPAH) and associated (APAH) varieties. Heterozygous mutations in BMPR2 can be detected in 50-70% of patients with FPAH and 10-40% of patients with IPAH. 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. Methods and Results The Bmpr2 gene was deleted in pulmonary endothelial cells (pECs) using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure (RVSP) were observed in mice with heterozygous (21.7 - 44.1 mmHg, median: 23.7 mmHg) and homozygous (20.7- 56.3 mmHg, median: 27 mmHg) conditional deletion of Bmpr2 in pECs in comparison with control mice (19.9 - 26.7 mmHg, median: 23 mmHg) at two to seven months of age. A subset of mice with RVSP greater than 30 mmHg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these high RVSP mice, expression of proteins involved in the pathogenesis of PAH, such as serotonin transporter and tenacin-C, were elevated in distal arteries, and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis. Conclusions Conditional hetero or homozygous Bmpr2 deletion in pECs predisposes mice to develop PAH.