Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: a possible role for peroxisome proliferator-activated receptors.
OBJECTIVE
Until recently, prostacyclin (PGI2) biological activities were thought to be exclusively mediated by cell surface receptors named IP. Recent studies have instead identified a novel pathway of PGI2 signaling, occurring through activation of peroxisome proliferator-activated receptors (PPARs) located in the nucleus. The availability of stable PGI2 analogs with different affinity for IP receptors and PPARs provides the possibility to test the importance and function of this dual pathway in vitro and in vivo. In this study, the in vivo angiogenic properties of different PGI2 analogs and the potential relationship between PPAR-mediated pathways, vascular endothelial growth factor (VEGF), and angiogenesis were investigated.


RESULTS
By using the murine corneal model of angiogenesis, we found that PGI2 analogs able to act on nuclear PPARs, such as iloprost and carbaprostacyclin (cPGI), induce angiogenesis in vivo. In contrast, cicaprost, a PGI2 analog that only acts on IP receptors, has no in vivo angiogenic activity. Interestingly, angiogenesis induced by iloprost and cPGI does not differ in extent and morphology from that induced by VEGF and is associated with local increment of VEGF mRNA expression and protein levels. Finally, iloprost-induced angiogenesis is significantly decreased by systemic inhibition of VEGF activity, obtained by gene transfer of a soluble form of the VEGF receptor Flt-1.


CONCLUSIONS
These data demonstrate that stable PGI2 analogs may have angiogenic properties in vivo, depending on their ability to act on PPARs. The resulting angiogenic process appears to be mediated by VEGF. These findings indicate that important physiological activities in the cardiovascular system, such as angiogenesis and VEGF induction, may be modulated by PGI2 through specific activation of the PPAR signaling pathway in vivo, with potentially important fundamental and clinical implications.
Pola
R
R
Laboratory of Vascular Biology and Genetics, Istituto di Patologia Speciale Medica, A Gemelli University Hospital, Largo A Gemelli 8, Rome 00168, Italy. rob_pola@hotmail.com
Gaetani
E
E
Flex
A
A
Aprahamian
T R
TR
Bosch-Marcé
M
M
Losordo
D W
DW
Smith
R C
RC
Pola
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D016285:Iloprost / Q000494:pharmacology*; D051379:Mice; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1
D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D011464:Epoprostenol; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains; D016285:Iloprost; C043867:cicaprost