Purchase this article with an account.
N. Sengupta, S. Caballero, E.W. Scott, R.N. Mames, S.M. Guthrie, M.B. Grant; Hemangioblast Activity of Stem Cells as Promoted by Injury and Modulated by Nitric Oxide in a Model of Retinal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2096.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have previously shown that adult hematopoietic stem cells (HSC) can function as hemangioblasts by making both blood cells and new retinal blood vessels (Nat Med 2002 8:607). Nitric oxide (NO) is one of the primary mediators of endothelial cell function and blood vessel formation. The role of NO in promoting angiogenesis has been controversial in part because of the complex regulation of NO, especially by the various NO synthetases (NOS). Besides vasodilatation, increased local NO stimulates proliferation and migration of endothelial cells. eNOS is constitutively expressed, promotes branching during vessel development, and mediates VEGF action. eNOS-deficient animals exhibit marked vascular pathology, decreased capillary density and decreased rates of angiogenesis. We assessed the role of NOS activity in the promotion of hematopoietic stem cell transdifferentiation into blood vessels. Methods: Wild type (WT), iNOS, and eNOS knockout (-/-) animals were transplanted with highly purified gfp+ stem cells. Long-term multilineage hematopoietic engraftment was confirmed at three months post-transplant by flow cytometry analysis of peripheral blood. Animals subsequently underwent our model of ischemic injury induction by intravitreal injection of rAAV-VEGF followed by laser ablation injury as previously described. Results: WT hemangioblast activity in adult iNOS-/- recipients resulted in the formation of small, highly branched blood vessels of donor origin. eNOS-/- recipients produced large, relatively unbranched blood vessels that were difficult to perfuse. eNOS-/- recipients also showed robust hemangioblast activity in tissues outside the retina, indicating that chronic injury is sufficient to induce HSC plasticity. Conclusions: Our earlier studies provided formal proof that endothelial progenitors are clonally derived and serially transplantable long-term reconstituting HSC. These experiments support that NOS activity at the site of vascular injury dictates the size and branch characteristics of new vessels formed in vivo. We demonstrated that modulation of the NO/NOS pathway alters the phenotype of blood vessels formed by hemangioblast activity in the retina.
This PDF is available to Subscribers Only