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Epoxide hydrolase inhibition induces an angiogenic response in the chick chorioallantoic membrane
Author(s) -
Valenzuela Cristian D.,
Ysasi Alexandra B.,
Belle Janeil,
Bennett Robert D.,
Wagner Willi,
Lee Kin Sing,
Rand Amy,
Barnych Bodgan,
Ackermann Maximilian,
Tsuda Akira,
Hammock Bruce D.,
Mentzer Steven J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1211.10
Subject(s) - chorioallantoic membrane , angiogenesis , epoxide hydrolase 2 , in vivo , chemistry , blood vessel , biochemistry , biology , microbiology and biotechnology , enzyme , endocrinology , cancer research
Omega‐6 and omega‐3 polyunsaturated fatty acids are precursors to chemical mediators of angiogenesis, important in many human diseases including cancer. Respectively, epoxyeicosatetraenoic acids (EETs) lead to pro‐angiogenic effects, whereas epoxydocosapentaenoic acids (EDP) are anti‐angiogenic. Epoxide hydrolase catalyzes the breakdown of these endogenously active intermediates, and has been identified as a promising target for angiogenic modulatory therapy. However, in vivo effects of soluble epoxide hydrolase inhibitor (sEHI) remain largely unexplored. The chick chorioallantoic membrane (CAM) is a well‐studied and accessible angiogenesis model. Here, we used the CAM at embryonic developmental day 10 to study the morphologic effects of topically applied sEHI and omega‐pathway intermediates on blood vessel formation (intussusceptive angiogenesis) and vascular lengthening leading to tortuous vessels (2 nd and 3 rd order veins and arteries). sEHI treatment for 72 hours significantly increased the density of intussusceptive pillars (1.21 per mm 2 versus 0.52 per mm 2 in controls; p<0.0001 two‐tailed Student's t‐Test), but did not increase the number, length, or degree of tortuous vessels (p=0.51, p=0.94, and p=0.33, respectively). sEHI applied together with the omega‐6 pro‐angiogenic intermediate 14,15‐EET led to an additional marked increase of pillars (2.86 per um 2 ; p<0.0001), as well as significantly increased tortuous vessels (0.72 per mm 2 versus 0.40 per mm 2 with sEHI alone, p<0.001). In contrast, sEHI applied with the omega‐3 anti‐angiogenic intermediate EDP resulted in the density of tortuous vessels being significantly lower compared to controls (0.182 versus 0.472 tortuous vessels per mm 2 , p<0.01). The pro‐ and anti‐angiogenic morphologic changes in response to omega‐6 and omega‐3 intermediates with soluble epoxide hydrolase inhibitor suggests this pathway is a potential target for therapeutic intervention in cancer and other diseases. Support or Funding Information The work presented here is supported by the National Institutes of Health T32 CA009535‐26 and R01 HL94567.Effects of omega‐3 and ‐6 pathway mediators on the chick chorioallantoic membrane. (A) Topical application of soluble epoxide hydrolase inhibitor (sEHI) with exogenous epoxyeicosatrienoic acid (EET) of the omega‐6 pathway led to pro‐angiogenic morphologic changes, and sEHI with epoxydocosapentaenoic acid (EDP) of the omega‐3 pathway led to anti‐angiogenic changes. Significant changes were found in frequency of (B) intussusceptive pillars and (C) tortuous vessel formation (*p<0.01 or less).