Prx1 controls vascular smooth muscle cell proliferation and tenascin-C expression and is upregulated with Prx2 in pulmonary vascular disease.
Prx1 and Prx2 are homeobox transcription factors expressed during vasculogenesis. To begin to elucidate how Prx1 and Prx2 are regulated and function in the adult vasculature, in situ hybridization studies were performed. Prx1 and Prx2 mRNAs were not detected in normal adult rat pulmonary arteries; however, both genes were induced with vascular disease, colocalizing to sites of tenascin-C (TN-C) expression. Because catabolism of the extracellular matrix (ECM) is a critical step in the development of vascular disease, we investigated whether changes in vascular smooth muscle cell (SMC)-ECM interactions regulate Prx1 and Prx2. A10 SMCs cultured on native type I collagen showed low levels of Prx1 and Prx2 mRNA expression, whereas cells cultured on denatured collagen showed higher levels of expression of both genes. At a functional level, transfection of SMCs with a Prx1 expression plasmid significantly increased their growth. Because TN-C also promotes SMC growth and its expression is also upregulated by denatured collagen, we tested and thereafter showed that Prx1 expression significantly enhances TN-C gene promoter activity 20-fold. Similar experiments conducted with truncated Prx1 proteins showed that the N-terminal portion and the homeodomain of Prx1 were necessary to induce the bulk of TN-C promoter activity. These findings support the hypothesis that Prx genes are regulated by changes in SMC adhesion and play key morphoregulatory roles during the development and progression of pulmonary vascular disease in adults.
Jones
F S
FS
Department of Neurobiology, Scripps Research Institute, La Jolla, California, USA. peter.jones@uchsc.edu
Meech
R
R
Edelman
D B
DB
Oakey
R J
RJ
Jones
P L
PL
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D018398:Homeodomain Proteins; D008164:Luminescent Proteins; C586264:Prrx2 protein, rat; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019063:Tenascin; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D008156:Luciferases