2-methoxyestradiol reduces cerebral vasospasm after 48 hours of experimental subarachnoid hemorrhage in rats.
2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and antiproapoptotic activities. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1alpha (HIF-1alpha). We hypothesized that hypoxia in the major cerebral arteries might activate a unique signaling pathway, hypoxia-inducible factor-1alpha (HIF-1alpha), to produce or enhance cerebral vasospasm after subarachnoid hemorrhage (SAH). Sprague-Dawley male rats (n = 70) were randomly divided into 5 groups: Sham operated, SAH without treatment, SAH treated with vehicle (DMSO), SAH treated with two HIF-1alpha inhibitors, 2ME2, and D609 (positive control of 2ME2). SAH model was produced by middle cerebral artery perforation. 2ME2 and D609 were administered intraperitoneal at 1 h after SAH; rats were sacrificed after 48 h of SAH. Thick blood clot was observed around basilar artery under arachnoids in all animals except Sham group; severe morphological vasospasm was observed in basilar arteries in SAH and SAH+DMSO rats, and the mild vasospasm in rats treated with 2ME2 and D609; 2ME2 and D609 reduced the activity of HIF-1alpha in the basilar arteries by HIF-1alpha DuoSet ELISA; reduce the expression of HIF-1alpha, VEGF, BNIP3 and PCNA in basilar arteries by Western blotting and immunohistochemical staining. In addition, it decreased the mortality and improved the neurological deficits. In conclusion, 2ME2 is a powerful agent to reduce cerebral vasospasm by inhibiting HIF-1alpha activity and the expression of VEGF as its downstream, suppressing endothelium and VSMCs apoptosis via BNIP3 pathway, and attenuating vasoproliferation.
Yan
Junhao
J
Department of Anatomy and Embryology, Peking University Health Science Center, Beijing, China 100083.
Chen
Chunhua
C
Lei
Jilian
J
Yang
Lei
L
Wang
Ke
K
Liu
Jun
J
Zhou
Changman
C
D000077584:2-Methoxyestradiol; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D009460:Neurologic Examination / Q000379:methods; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D050257:Tubulin Modulators / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality
C505650:BNIP3 protein, rat; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077584:2-Methoxyestradiol