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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/H677    most recent 91519.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Song, Y. Articles by Zhang, Y.-Y. PubMed PubMed Citation Articles by Song, Y. Articles by Zhang, Y.-Y.

Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

¹Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston; ²Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston; and ³Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts

Submitted 21 December 2007 ; accepted in final form 2 June 2008

Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2^+/–) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2^+/– mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT+Ad5LO). After the challenge (1 wk), BMPR2^+/– mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wild-type mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2^+/– 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 BMPR2^+/– and wild-type mice and largely recovered in wild-type (50–80%) but not BMPR2^+/– lungs (30–50%) at 3 wk after the challenge. Macrophage inflammatory protein-1 and fractalkine receptor expression doubled in BMPR2^+/– compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-β receptors, in the challenged BMPR2^+/– 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^+/– lungs than the wild-type lungs. These data show that BMPR2^+/– mice are more sensitive to MCT+Ad5LO-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

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