Abstract
The precise mechanisms of SDF‐1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF‐1 and CXCR4. In the current study, we demonstrated SDF‐1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF‐1 expression in wild‐type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF‐1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF‐1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF‐1 application and two times less after blocking this pathway. Bone marrow‐derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF‐1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF‐1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling.
Highlights
Angiogenesis is essential for normal embryonic development, and plays a key role in pathological conditions related to tumour growth and ischaemic cardiovascular diseases
Pharmacological inhibition of SDF‐1/CXCR4 signalling by small CXCR4 antagonist AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in GSI treated samples of chicken area vasculosa (CAV)
We confirm that extravasation and recruitment of bone marrow‐derived cells (BMDC) is due to increased expression of SDF‐1, and occurs concomitantly with intussusceptive angiogenesis both in the CAV and in the mouse model
Summary
Angiogenesis is essential for normal embryonic development, and plays a key role in pathological conditions related to tumour growth and ischaemic cardiovascular diseases This is a complex process in‐ volving essential signalling pathways such as VEGF, basic fibroblast growth factor (bFGF) and Notch in vasculature. Of major significance is the involvement of intussusceptive angiogenesis in pathological conditions such as liver nodular hyperplasia,[24] in the vasculature of experimental and clinical tumours,[25,26] in liver metastasis,[29] in metastatic tumours of the brain[30] and in breast cancer progression[31] among others Despite this variety of roles, attributed to intussusceptive angio‐ genic, most of the current research is focused on sprouting angio‐ genesis because the latter mechanism has been known since many decades ago and there are many experimental models related to sprouting angiogenesis. We provide evidence that intussusceptive angiogenesis is regulated by SDF‐1/CXCR4 signal‐ ling and suggest some intussusceptive angiogenic roles for CXCR4 and Tie‐2 positive bone marrow‐derived mononuclear cells (BMDC)
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