Neovascularization in the pulmonary endothelium is regulated by the endosome: Rab4-mediated trafficking and p18-dependent signaling

Research output: Contribution to journalArticle


External Institution(s)

  • Brown University


Original languageEnglish (US)
Pages (from-to)L700-L709
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number7
StatusPublished - Sep 1 2015


Neovascularization, the formation of new blood vessels, requires multiple processes including vascular leak, migration, and adhesion. Endosomal proteins, such as Rabs, regulate trafficking of key signaling proteins involved in neovascularization. The novel endosome protein, p18, enhances vascular endothelial (VE)-cadherin recycling from early endosome to cell junction to improve pulmonary endothelial barrier function. Since endothelial barrier integrity is vital in neovascularization, we sought to elucidate the role for endosome proteins p18 and Rab4, Rab7, and Rab9 in the process of vessel formation within the pulmonary vasculature. Overexpression of wild-type p18 (p18wt), but not the nonendosomal-binding mutant (p18N39), significantly increased lung microvascular endothelial cell migration, adhesion, and both in vitro and in vivo tube formation. Chemical inhibition of mTOR or p38 attenuated the proneovascularization role of p18wt. Similar to the effect of p18wt, overexpression of prorecycling wildtype (Rab4WT) and endosome-anchored (Rab4Q67L) Rab4 enhanced neovascularization processes, whereas molecular inhibition of Rab4, by using the nonendosomal-binding mutant (Rab4S22N) attenuated VEGF-induced neovascularization. Unlike p18, Rab4-induced neovascularization was independent of mTOR or p38 inhibition but was dependent on p18 expression. This study shows for the first time that neovascularization within the pulmonary vasculature is dependent on the prorecycling endocytic proteins Rab4 and p18. Key words endocytosis; endothelium; mTOR; p38; neovascularization; LAMTOR; pulmonary.

    Research areas

  • Endocytosis, Endothelium, LAM-TOR, Neovascularization, Pulmonary, mTOR, p38

Citation formats



Chichger, H, Braza, J, Duong, H, Stark, M & Harrington, EO 2015, 'Neovascularization in the pulmonary endothelium is regulated by the endosome: Rab4-mediated trafficking and p18-dependent signaling', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 309, no. 7, pp. L700-L709.