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Regulation and Functions of the Paired-Related Homeobox Gene PRX1 in Pulmonary Vascular Development and Disease^*

K. Ihida-Stansbury, PhD; D.M. McKean, MS; S.A. Gebb, PhD; J.F. Martin, MD, PhD; T. Stevens, PhD; R. Nemenoff, PhD; J. Vaughn, BS; K. Lane, PhD; J. Loyd, MD, FCCP; L. Wheeler, BS; N.W. Morrell, MD; D. Ivy and P.L. Jones, PhD

^* From the Departments of Pediatrics (Drs. Ihida-Stansbury, McKean, Vaughn, Ivy, and Jones) and Medicine (Drs. Gebb and Nemenoff), University of Colorado Health Sciences Center, Denver, CO; Institute of Biosciences and Technology (Dr. Martin), Texas A & M University, Houston, TX; the Center for Lung Biology (Dr. Stevens), University of South Alabama, Mobile, AL; Vanderbilt University (Drs. Lane, Loyd, and Wheeler), Nashville, TN; and Department of Medicine (Dr. Morrell), Cambridge University, Cambridge, UK. These authors contributed equally to this article.

Correspondence to: Peter L. Jones, PhD, Institute for Medicine and Engineering, 1022 Vangelos Research Building, 3340 Smith Walk, Philadelphia, PA 19104-6384; e-mail: jonespl{at}mail.med.upenn.edu

Pulmonary vascular development relies on vasculogenesis and angiogenesis. In both instances, differentiating pulmonary endothelial cells (ECs) must connect to form vascular networks. Here, we provide evidence indicating that the paired-related homeobox gene Prx1 promotes both distal vasculogenesis and vascular network formation, and we identify a potential mechanism by which this occurs. During embryonic lung development, Prx1 was expressed by differentiating ECs emerging within the distal mesenchyme, as well as in ECs forming networks, suggesting that Prx1 might participate in either of these processes. In keeping with this, cellular transfection studies showed that Prx1-transformed EC precursors derived from the lung mesenchyme not only acquire an EC-like phenotype, but that these cells are also able to form polarized, three-dimensional vascular networks on basement membrane matrix (Matrigel; BD Biosciences; San Jose, CA) in a manner that depends on tenascin-C (TN-C), a proangiogenic extracellular matrix glycoprotein that is induced by Prx1. Consistent with these findings, lungs from newborn Prx1-null mice, which are cyanotic and die shortly after birth from respiratory distress, expressed decreased levels of TN-C and contained markedly reduced numbers of distal blood vessels when compared to Prx1-wild-type littermates.

Because we have already shown that Prx1 and TN-C promote fibroblast migration and vascular smooth muscle cell (SMC) proliferation, we next asked whether these genes also play a role in primary pulmonary hypertension (PPH), a disease that may be characterized by the increased proliferation and/or migration of adventitial fibroblasts, vascular SMCs, and endothelial cells. Immunohistochemical studies revealed that Prx1 and TN-C are induced and colocalize in pulmonary vascular lesions in human subjects with familial PPH, the genesis of which has been linked to mutations in bone morphogenetic protein (BMP) type II receptors. In contrast, normal adult lung vessels did not express Prx1 and TN-C. To determine how mutated BMP type II receptors induce Prx1 and TN-C, we first performed gene microarray and reverse-transcriptase polymerase chain reaction studies using cultured vascular SMCs that were isolated from healthy subjects and patients with PPH harboring type II receptor mutations; whereas normal SMCs expressed very low levels of Prx1 and TN-C messenger RNA, PPH SMCs expressed increased levels of these messenger RNAs. Next, we cloned the Prx1 gene promoter and used it in cellular transfection studies involving normal and PPH SMCs to show that mutated BMP type II receptors are capable of regulating Prx1 gene expression at the transcriptional level. Currently, we are utilizing both the Prx1 and TN-C gene promoters as platforms to identify cis and trans-acting factors, as well as upstream signaling mediators that are called forth in PPH associated with BMP type II receptor mutations. It is hoped that these studies will lead to the identification of novel targets, which include both transcriptional and extracellular mediators of the PPH phenotype.

	Footnotes

 
Abbreviations: BMP = bone morphogenetic protein; EC = endothelial cell; PPH = primary pulmonary hypertension; SMC = smooth muscle cell; TN-C = tenascin-C

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ihida-Stansbury, K. Articles by Jones, P.L. Search for Related Content PubMed PubMed Citation Articles by Ihida-Stansbury, K. Articles by Jones, P.L.