FGF2-dependent neovascularization of subcutaneous Matrigel plugs is initiated by bone marrow-derived pericytes and macrophages.
Vessel-like networks are quickly formed in subcutaneous FGF2-supplemented Matrigel plugs by two cell types: NG2(+) pericytes and F4/80(+) macrophages. Although not detected in these networks until 7 days after plug implantation, the appearance of CD31(+) endothelial cells marks the onset of vessel perfusion and the establishment of mature vessel morphology, with endothelial cells invested tightly by pericytes and more loosely by macrophages. Evidence that mature vessels develop from pericyte/macrophage networks comes from experiments in which 5-day plugs are transplanted into EGFP(+) recipients and allowed to mature. Fewer than 5% of pericytes in mature vessels are EGFP(+) in this paradigm, demonstrating their presence in the networks prior to plug transplantation. Endothelial cells represent the major vascular cell type recruited during later stages of vessel maturation. Bone marrow transplantation using EGFP(+) donors establishes that almost all macrophages and more than half of the pericytes in Matrigel vessels are derived from the bone marrow. By contrast, only 10% of endothelial cells exhibit a bone marrow origin. The vasculogenic, rather than angiogenic, nature of this neovascularization process is unique in that it is initiated by pericyte and macrophage progenitors, with endothelial cell recruitment occurring as a later step in the maturation process.
Tigges
Ulrich
U
Burnham Institute for Medical Research, Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. utigges@burnham.org
Hyer
Elizabeth Gore
EG
Scharf
Jeffrey
J
Stallcup
William B
WB
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000067696:Ataxin-1; D000067528:Ataxins; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005434:Flow Cytometry; D007797:Laminin / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010477:Perfusion; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
D018952:Antigens, CD34; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015415:Biomarkers; D004338:Drug Combinations; D007797:Laminin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen