Xue Qi, Nagy Janice A, Manseau Eleanor J, Phung Thuy L, Dvorak Harold F, Benjamin Laura E
Center for Vascular Biology and the Department of Pathology at the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Arterioscler Thromb Vasc Biol. 2009 Aug;29(8):1172-8. doi: 10.1161/ATVBAHA.109.185918. Epub 2009 May 14.
We evaluated the stages of VEGF-A(164) driven angiogenesis that are inhibited by therapeutic doses of rapamycin and the potential role of S6K1 in that response.
We assessed the effects of rapamycin on the several stages of angiogensis and lymphangiogenesis induced with an adenovirus expressing VEGF-A(164) (Ad-VEGF-A(164)) in the ears of adult nude mice. Rapamycin (0.5 mg/kg/d) effectively inhibited mTOR and downstream S6K1 signaling and partially inhibited Akt signaling, likely through effects on TORC2. The earliest stages of angiogenesis, including mother vessel formation and increased vascular permeability, were strikingly inhibited by rapamycin, as was subsequent formation of daughter glomeruloid microvasular proliferations. However, later stage formation of vascular malformations and lymphangiogenesis were unaffected. Retrovirally delivered isoforms and shRNAs demonstrated that S6K1 signaling plays an important role in early VEGF-A(164)-angiogenesis.
Rapamycin potently inhibited early and mid stages of VEGF-A(164)-driven angiogenesis, but not late-stage angiogenesis or lymphangiogenesis. Rapamycin decreased phosphorylation of both Akt and S6, suggesting that both the TORC1 and TORC2 pathways are impacted. Inhibition of S6K1 signaling downstream of mTOR is a major component of the antiangiogenesis action of rapamycin.
我们评估了治疗剂量的雷帕霉素所抑制的VEGF-A(164)驱动的血管生成阶段,以及S6K1在该反应中的潜在作用。
我们评估了雷帕霉素对成年裸鼠耳部由表达VEGF-A(164)的腺病毒(Ad-VEGF-A(164))诱导的血管生成和淋巴管生成的几个阶段的影响。雷帕霉素(0.5mg/kg/d)有效抑制mTOR和下游S6K1信号传导,并部分抑制Akt信号传导,可能是通过对TORC2的作用。血管生成的最早阶段,包括母血管形成和血管通透性增加,被雷帕霉素显著抑制,随后的子肾小球样微血管增殖形成也被抑制。然而,后期血管畸形的形成和淋巴管生成未受影响。逆转录病毒传递的异构体和短发夹RNA表明,S6K1信号传导在早期VEGF-A(164)介导的血管生成中起重要作用。
雷帕霉素有效抑制VEGF-A(164)驱动的血管生成的早期和中期阶段,但不抑制晚期血管生成或淋巴管生成。雷帕霉素降低了Akt和S6的磷酸化,表明TORC1和TORC2途径均受到影响。抑制mTOR下游的S6K1信号传导是雷帕霉素抗血管生成作用的主要组成部分。