Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic mice

Yang Zhang, Jian Liu, Xiao Yu Tian, Wing Tak Wong, Yangchao Chen, Li Wang, Jiangyun Luo, Wai San Cheang, Chi Wai Lau, Kin Ming Kwan, Nanping Wang, Xiaoqiang Yao, Yu Huang

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


OBJECTIVE - Bone morphogenic protein 4 (BMP4) is involved in the development of endothelial dysfunction in hypertension. This study investigated whether the inhibition of BMP4 signaling improves endothelial function in db/db diabetic mice. APPROACH AND RESULTS - Male db/db mice were treated with noggin via osmotic pump infusion (1 μg/[h·kg]) for 2 weeks. Adenovirus BMP4-short hairpin RNA was introduced via tail vein injection at a dosage of 10 pfu/mouse and its effects were examined 7 days after. Vasoreactivity was studied on wire and pressure myograph. Both noggin treatment and adenovirus BMP4-short hairpin RNA transduction improved endothelium-dependent relaxations in aortae and flow-mediated dilatation in mesenteric arteries of db/db mice. Ex vivo treatment with BMP4 inhibitors and adenovirus BMP4-short hairpin RNA rescued the impaired endothelium-dependent relaxations in db/db mouse aortae and reduced reactive oxygen species overproduction determined by dihydroethidium staining, CM-H2DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortae, and also in ex vivo cultured C57BL/6 mouse aortae or primary mouse aortic endothelial cells treated with high glucose. Likewise, activin receptor-like kinase 3 silencing by short hairpin RNA lentivirus improved endothelium-dependent relaxations in db/db mouse aortae accompanied by reactive oxygen species inhibition in endothelial cells. In addition, noggin reduced BMP4 upregulation in high-glucose-treated endothelial cells and in C57BL/6 mouse aortae and in aortae from db/db mice. CONCLUSIONS - Inhibition of BMP4/activin receptor-like kinase 3/reactive oxygen species signaling improved endothelial function in diabetic mice through limiting oxidative stress in endothelium. Inhibiting BMP4 cascade can become another potential therapeutic strategy against diabetic vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)152-159
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number1
StatePublished - Jan 2014


  • Bone morphogenetic protein 4, mouse
  • Diabetes mellitus
  • Endothelial dysfunction
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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