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Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes
Author(s) -
Kunduzova O.,
Alet N.,
DelesqueTouchard N.,
Millet L.,
CastanLaurell I.,
Muller C.,
Dray C.,
Schaeffer P.,
Herault J. P.,
Savi P.,
Bono F.,
Valet P.
Publication year - 2008
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/fj.07-104018
Subject(s) - apelin , adipose tissue , angiogenesis , medicine , endocrinology , transplantation , white adipose tissue , matrigel , biology , endothelial stem cell , chemistry , microbiology and biotechnology , receptor , biochemistry , in vitro
Adipose tissue is an active endocrine organ that produces a variety of secretory factors involved in the initiation of angiogenic processes. The bioactive peptide apelin is the endogenous ligand of the G protein‐coupled receptor, APJ. Here we investi gated the potential role of apelin and its receptor, APJ, in the angiogenic responses of human endothelial cells and the development of a functional vascular network in a model of adipose tissue development in mice. Treatment of human umbilical vein endothelial cells with apelin dose‐dependently increased angiogenic re sponses, including endothelial cell migration, prolifer ation, and Matrigel® capillary tubelike structure forma tion. These endothelial effects of apelin were due to activation of APJ, because siRNA directed against APJ, which led to long‐lasting down‐regulation of APJ mRNA, abolished cell migration induced by apelin in contrast to control nonsilencing siRNA. Hypoxia upregulated the expression of apelin in 3T3F442A adipo cytes, and we therefore determined whether apelin could play a role in adipose tissue angiogenesis in vivo . Epididymal white adipose tissue (EWAT) transplanta tion was performed as a model of adipose tissue angiogenesis. Transplantation led to increased apelin mRNA levels 2 and 5 days after transplantation associ ated with tissue hypoxia, as evidenced by hydroxyprobe staining on tissue sections. Graft revascularization evolved in parallel, as the first functional vessels in EWAT grafts were observed 2 days after transplantation and a strong angiogenic response was apparent on day 14. This was confirmed by determination of graft hemoglobin levels, which are indicative of functional vascularization and were strongly increased 5 and 14 days after transplantation. The role of apelin in the graft neovascularization was then assessed by local delivery of stable complex apelin‐targeting siRNA lead ing to dramatically reduced apelin mRNA levels and vascularization (quantified by hemogloblin content) in grafted EWAT on day 5 when compared with control siRNA. Taken together, our data provide the first evidence that apelin/APJ signaling pathways play a critical role in the development of the functional vascular network in adipose tissue. In addition, we have shown that adipocyte‐derived apelin can be up‐regu lated by hypoxia. These findings provide novel insights into the complex relationship between adipose tissue and endothelial vascular function and may lead to new therapeutic strategies to modulate angiogenesis.— Kunduzova, O., Alet, N., Delesque‐Touchard, N., Millet, L., Castan‐Laurell, I., Muller, C., Dray, C., Schaeffer, P., Herault, J. P., Savi, P., Bono, F., Valet, P. Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J. 22, 4146–4153 (2008)