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1 Brigham and Women's Hospital, and Harvard Medical School
2 Brigham and Women's Hospital
3 Massachusetts General Hospital
4 Boston University School of Medicine
5 Brigham and Women's Hospital, Harvard
* To whom correspondence should be addressed. E-mail: yyzhang{at}rics.bwh.harvard.edu.
Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2+/-) mice have a similar genetic trait as that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2+/- mice, this study challenged the mice with two injections of monocrotaline combined with an intratracheal instillation of recombinant adenovirus expressing 5-lipoxygenase (MCT+Ad5LO). A week after the challenge, BMPR2+/- mice exhibited a doubling of right ventricular systolic pressure, which was greater than that of wildtype mice and remained elevated for three weeks before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2+/- lungs at 2 week after the challenge and became severe at 3 weeks. 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 pretreatment levels at 1 week after the challenge in both BMPR2+/- and wildtype mice, and largely returned toward normal in wildtype (50-80%) but not BMPR2+/- lungs (30-50%) at 3 weeks. MIP-1
and fractalkine receptor expression was increased ~2-fold in BMPR2+/- compared with wildtype lungs. Expression of type I and II BMP receptors, but not TGF-
receptors, in the challenged BMPR2+/- and wildtype lungs showed a similar pattern as that of endothelial markers. These data showed that BMPR2+/- mice are more sensitive to MCT+Ad5LO-induced pulmonary hypertension than wildtype mice. Impaired pulmonary endothelial regeneration and enhanced immune response may be the underlying causes of this sensitivity.
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