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

84Citations
Citations of this article
62Readers
Mendeley users who have this article in their library.

This article is free to access.

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 wildtype 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-1α 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. Copyright © 2008 the American Physiological Society.

Cite

CITATION STYLE

APA

Song, Y., Coleman, L., Shi, J., Beppu, H., Sato, K., Walsh, K., … Zhang, Y. Y. (2008). Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. American Journal of Physiology - Heart and Circulatory Physiology, 295(2). https://doi.org/10.1152/ajpheart.91519.2007

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free