0
Articles |

Suppression of Type II Bone Morphogenic Protein Receptor in Vascular Smooth Muscle Induces Pulmonary Arterial Hypertension in Transgenic Mice*

James West, PhD; Yuji Tada, MD; Karen A. Fagan, MD; Wolfgang Steudel, MD; Brian W. Fouty, MD; Julie Wright Harral, MS; Marloes Miller, MS; John Ozimek; Rubin M. Tuder, MD; David M. Rodman, MD
Author and Funding Information

*From the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: James West, PhD, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box B133, 4200 E Ninth Ave, Denver, CO; e-mail: james.west@uchsc.edu



Chest. 2005;128(6_suppl):553S. doi:10.1378/chest.128.6_suppl.553S
Text Size: A A A
Published online

Extract

Bone morphogenic proteins have a well-described role in development, and targeted disruption of the pathway in mice results in fetal lethality prior to gastrulation. Thus, it was surprising when the gene responsible for the majority of cases of hereditary pulmonary arterial hypertension (PAH) was identified as the type II bone morphogenic protein receptor (BMPRII). We therefore constructed a conditional, smooth-muscle-specific transgenic mouse expressing a dominant-negative BMPRII mutation identified in a family with PAH (SM22-tet-dnBMPRII mice). We then addressed the following questions: (1) is loss of functional BMPRII in smooth muscle sufficient to produce the disease phenotype, and (2) despite generalized smooth-muscle expression of the mutant gene, are abnormalities restricted to the pulmonary circulation? Just as is seen in humans, SM22-tetdnBMPRII mice acquired severe PAH at sea level, associated with increased muscularization of small pulmonary arteries with no abnormality in systemic BP. Analysis of gene expression patterns by GeneChip (Affymetrix; Santa Clara, CA) showed a pattern of gene regulation markedly different from that in hypoxic pulmonary hypertension, including differential regulation of genes involved in cytoskeletal rearrangement, inflammation, and vascular tone. The mice were hyperresponsive to hypoxia, becoming even more severely hypertensive when kept at Denver altitude. In conclusion, we report the first transgenic model of PAH, establishing that selective smooth-muscle expression of a mutant BMPRII gene found in a family with PAH recapitulates the disease phenotype in transgenic mice.

First Page Preview

View Large
First page PDF preview

Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Figures

Tables

References

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543