Background-Bone morphogenetic protein receptor-2 (BMPR2)-heterozygous, mutant (BMPR2 ϩ/Ϫ ) mice have a genetic trait similar to that of certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of BMPR2 in the development of IPAH, we examined the phenotype of BMPR2 ϩ/Ϫ mice and their response to inflammatory stress. Methods and Results-BMPR2ϩ/Ϫ mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wild-type mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO), BMPR2 ϩ/Ϫ mice exhibited significantly higher RVSP than wild-type mice. The increase of RVSP occurred in the first 2 weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in BMPR2 ϩ/Ϫ mice 4 weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and PGE 2 were all increased to a similar degree in both BMPR2 ϩ/Ϫ and wild-type mice during 5LO transgene expression, whereas urinary endothelin-1 remained undetectable. Urinary thromboxane A 2 metabolites, in contrast, were significantly higher in BMPR2 ϩ/Ϫ than in wild-type mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and soluble P-selectin showed a trend toward higher concentrations in BMPR2 ϩ/Ϫ than wild-type mice. Cell culture studies found that BMP treatment reduced interleukin-1␤-stimulated thromboxane A 2 production in the pulmonary epithelial cell line A549. Conclusions-BMPR2ϩ/Ϫ mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A 2 production, and vascular remodeling than wild-type mice.

. Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol 295: H677-H690, 2008. First published June 13, 2008 doi:10.1152/ajpheart.91519.2007.-Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2 ϩ/Ϫ ) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2ϩ/Ϫ mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replicationdeficient adenovirus expressing 5-lipoxygenase (MCTϩAd5LO). After the challenge (1 wk), BMPR2 ϩ/Ϫ mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wildtype mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2 ϩ/Ϫ lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20 -40% of original levels at 1 wk after the challenge in both BMPR2ϩ/Ϫ and wild-type mice and largely recovered in wild-type (50 -80%) but not BMPR2 ϩ/Ϫ lungs (30 -50%) at 3 wk after the challenge. Macrophage inflammatory protein-1␣ and fractalkine receptor expression doubled in BMPR2ϩ/Ϫ compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-␤ receptors, in the challenged BMPR2 ϩ/Ϫ and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2 ϩ/Ϫ lungs than the wild-type lungs. These data show that BMPR2 ϩ/Ϫ mice are more sensitive to MCTϩAd5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension.heterozygous bone morphogenetic protein receptor-2 knockout mice HETEROZYGOUS GERMLINE MUTATIONS of bone morphogenetic protein receptor-2 (BMPR2) have been found in patients with idiopathic pulmonary arterial hypertension (IPAH) (10,20,46), a progressive disease characterized by extensive remodeling of the pulmonary arterioles and persistent increase of pulmonary artery pressure of unknown cause. Nearly 70% of familial IPAH and 20% of sporadic IPAH patients have a heterozygous BMPR2 mutation (1), but the chance of developing pulmonary arterial hypertension (PAH) among the BMPR2 mutant family members is only 10 -20% (32). Therefore, additional factors are believed to be required for the development of PAH in the BMPR2 mutant carriers.The BMPR2 gene encodes BMPR-II, which forms a complex with ...