The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells.
We have previously established a model inducing hematopoietic stem cell (HSC) production of circulating endothelial progenitor cells (EPCs) to revascularize ischemic injury in adult mouse retina. The unique vascular environment of the retina results in new blood vessel formation primarily from HSC-derived EPCs. Using mice deficient (-/-) in inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), we show that vessel phenotype resulting from hemangioblast activity can be altered by modulation of the NO/NOS pathway. iNOS-/- or eNOS-/- animals were engrafted with wild-type (WT) HSCs expressing green fluorescence protein (gfp+) and subjected to our adult retinal ischemia model. WT hemangioblast activity in adult iNOS-/- recipients resulted in the formation of highly branched blood vessels of donor origin, which were readily perfused indicating functionality. In contrast, eNOS-/- recipients produced relatively unbranched blood vessels with significant donor contribution that were difficult to perfuse, indicating poor functionality. Furthermore, eNOS-/- chimeras had extensive gfp+ HSC contribution throughout their vasculature without additional injury. This neovascularization, via EPCs derived from the transplanted HSCs, reveals that the NO pathway can modulate EPC activity and plays a critical role in both blood vessel formation in response to injury and normal endothelial cell maintenance.
Guthrie
Steven M
SM
Program in Stem Cell Biology and Regenerative Medicine, University of Florida Shand's Cancer Center, Academic Research Building R4-254, 1600 SW Archer Rd, Gainesville, FL 32610, USA.
Curtis
Lisa M
LM
Mames
Robert N
RN
Simon
Gregory G
GG
Grant
Maria B
MB
Scott
Edward W
EW
D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D007511:Ischemia; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012164:Retinal Diseases; D012171:Retinal Vessels / Q000254:growth & development
D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse