Interactions of PPAR-alpha and adenosine receptors in hypoxia-induced angiogenesis.
Hypoxia and adenosine are known to upregulate angiogenesis; however, the role of peroxisome proliferator-activated receptor alpha (PPARα) in angiogenesis is controversial. Using transgenic Tg(fli-1:EGFP) zebrafish embryos, interactions of PPARα and adenosine receptors in angiogenesis were evaluated under hypoxic conditions. Epifluorescent microscopy was used to assess angiogenesis by counting the number of intersegmental (ISV) and dorsal longitudinal anastomotic vessel (DLAV) at 28 h post-fertilization (hpf). Hypoxia (6h) stimulated angiogenesis as the number of ISV and DLAV increased by 18-fold (p<0.01) and 100 ± 8% (p<0.001), respectively, at 28 hpf. Under normoxic and hypoxic conditions, WY-14643 (10 μM), a PPARα activator, stimulated angiogenesis at 28 hpf, while MK-886 (0.5 μM), an antagonist of PPARα, attenuated these effects. Compared to normoxic condition, adenosine receptor activation with NECA (10 μM) promoted angiogenesis more effectively under hypoxic conditions. Involvement of A2B receptor was implied in hypoxia-induced angiogenesis as MRS-1706 (10nM), a selective A2B antagonist attenuated NECA (10 μM)-induced angiogenesis. NECA- or WY-14643-induced angiogenesis was also inhibited by miconazole (0.1 μM), an inhibitor of epoxygenase dependent production of eicosatrienoic acid (EET) epoxide. Thus, we conclude that: activation of PPARα promoted angiogenesis just as activation of A2B receptors through an epoxide dependent mechanism.
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA. Electronic address: yas0464@yahoo.com.
Yasmeen Q
YQ
Rizvi
Chander S
CS
Mehta
Adebayo
A
Oyekan
D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*; D047493:PPAR alpha / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology; D002722:Chlorobenzenes
D019830:Adenosine-5'-(N-ethylcarboxamide); D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D008825:Miconazole; D047493:PPAR alpha; D011687:Purines; D011743:Pyrimidines; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; C496145:N-(4-acetylphenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy)acetamide; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid; C572289:eicosenoic acid
5′-N-ethylcarboxamidoadenosine; Adenosine receptors; Angiogenesis; CYP2C9; DLAV; EET; Eicosatrienoic acid; HIF-1α; IL-8; ISV; NECA; PGAR; PPARα; PPARγ; PPARγ angiopoietin-related gene; TSP-1; Tg(fli-1:EGFP); Zebrafish; cytochrome P450 2C9; dorsal longitudinal anastomotic vessel; eicosatrienoic acid; hour post-fertilization; hpf; hypoxia-inducible factor-1 alpha; interleukin-8; intersegmental vessel; peroxisome proliferator-activated receptor alpha; peroxisome proliferator-activated receptor gamma; thrombospondin-1; transgenic friendly leukemia integration-1 enhanced green fluorescent protein