Der Einfluß von Leptin auf die Freisetzung endothelialer Vorläuferzellen aus dem Knochenmark

Der Einfluß von Leptin auf die Freisetzung endothelialer Vorläuferzellen aus dem Knochenmark

The impact of leptin on the mobilisation of endothelial progenitor cells out of the bone marrow

Susanne Stein

Doctoral thesis

Date of Examination: 2014-07-08

Date of issue: 2014-06-25

Advisor: Schroeter, Marco PD Dr.

Referee: Schäfer, Katrin Prof. Dr.

Referee: Legler, Tobias Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-5EFA-E

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Abstract

English

Objective− Bone marrow progenitor cells participate in new vessel formation and endothelial repair, and both processes may be modulated by the adipokine leptin. The leptin receptor (ObR) is expressed on hematopoeitic cells, however, the effects of leptin on bone marrow (BM)-derived progenitor cells and their angiogenic potential are unknown. Methods and Results− In wildtype (WT) mice, short term (over 5 consecutive days) intraperitoneal injections of leptin increased neovascularization after hindlimb ischemia, as determined by the quantification of CD31+ endothelial cells, and analysis of Green Fluorescent Protein chimeric WT mice confirmed their BM origin. Moreover, leptin increased the number of circulating BM-derived sca1+/flk1+ vascular progenitor cells (P<0.05). PCR analysis, flow cytometry and immunohistochemistry of BM cells confirmed expression of ObR, and the effects of the adipokine on the mobilization of sca1+/flk1+ or on ischemia-induced angiogenesis were abolished in mice transplanted with BM from ObR-deficient db/db mice. Mechanistically, leptin administration increased NADPH subunit (NOX)-2 and matrix metalloproteinase (MMP)-9 expression within the BM (P<0.05 and <0.01, respectively) as well as plasma levels of the potent stem cell-mobilizing factor sKitL (P<0.001). Importantly, the effects of leptin were abolished in mice transplanted with BM from db/db mice, but also in mice lacking NOX2. Conclusions− Our findings suggest that the angiogenic effects of leptin in vivo are mediated by flk1+ vascular progenitor cells mobilized from the bone marrow in response to ObR-mediated activation of specific signaling pathways involving NOX2, MMP9 and sKitL.

Keywords: angiogenesis; fetal liver kinase-1; ischemia; leptin; mobilization; NADPH oxidase; sKitL; vascular progenitor cells;