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Published on: January 16, 2013
Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice
Yanli Song1, Laura Coleman, Jianru Shi
1Cardiovascular Division, Dept. of Medicine, Brigham and Women's Hosiptal and Harvard Medical School, 77 Ave. Louis Pasteur, NRB 630, Boston, MA 02115, USA.
Abstract:
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-1alpha 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-beta 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.
Insights
BMPR2(+/-) mice are more susceptible to pulmonary hypertension induced by monocrotaline and adenovirus. This heightened sensitivity is linked to greater endothelial injury and inflammation, contributing to persistent pulmonary hypertension.
Area of Science:
- Cardiovascular Biology
- Pulmonary Medicine
- Genetics
Background:
- Idiopathic pulmonary arterial hypertension (IPAH) is a severe condition with genetic links.
- Bone morphogenetic protein receptor-II (BMPR2) heterozygous knockout mice share genetic similarities with some IPAH patients.
- Understanding BMPR2's role in pulmonary hypertension pathogenesis is crucial.
Purpose of the Study:
- To investigate the impact of pulmonary endothelial injury in BMPR2(+/-) mice.
- To model IPAH using a combined challenge of monocrotaline and adenovirus expressing 5-lipoxygenase (MCT+Ad5LO).
- To assess the BMPR2(+/-) mice's response to induced pulmonary hypertension.
Main Methods:
- BMPR2(+/-) and wild-type mice were challenged with MCT+Ad5LO.
- Right ventricular systolic pressure was monitored.
- Pulmonary arteriole morphology and cellular infiltration were analyzed.
- Gene expression of endothelial markers and inflammatory mediators was quantified using real-time PCR.
- Apoptotic responses were assessed.
Main Results:
- BMPR2(+/-) mice showed significantly elevated right ventricular systolic pressure compared to wild-type mice post-challenge.
- Pulmonary arterioles in BMPR2(+/-) mice exhibited severe muscularization and thickening with increased inflammatory cell infiltration.
- Endothelial cell marker expression was significantly reduced and less recovered in BMPR2(+/-) lungs.
- Expression of inflammatory mediators like macrophage inflammatory protein-1alpha and fractalkine receptor was elevated in BMPR2(+/-) lungs.
- BMPR2(+/-) lungs displayed greater apoptosis following the challenge.
Conclusions:
- BMPR2(+/-) mice are more sensitive to MCT+Ad5LO-induced pulmonary hypertension.
- Increased endothelial injury and an amplified inflammatory response contribute to this sensitivity.
- BMPR2 heterozygosity, in conjunction with endothelial damage and inflammation, promotes persistent pulmonary hypertension.
