title: Tie2 activation contributes to hemangiogenic regeneration after myelosuppression.
abstract: Chemotherapy- or radiation-induced myelosuppression results in apoptosis of cycling hematopoietic cells and induces regression of bone marrow (BM) sinusoidal vessels. Moreover, timely regeneration of BM neovessels is essential for reconstitution of hematopoiesis. However, the identity of angiogenic factors that support reconstitution of BM's vasculature is unknown. Here, we demonstrate that angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) signaling contributes to the assembly and remodeling of BM neovessels after myelosuppression. Using transgenic mice where the Tie2 promoter drives the reporter LacZ gene (Tie2-LacZ), we demonstrate that at steady state, there was minimal expression of Tie2 in the BM vasculature. However, after 5-fluorouracil (5-FU) treatment, there was a rapid increase in plasma vascular endothelial growth factor A (VEGF-A) levels and expansion of Tie2-positive neovessels. Inhibition of Tie2 resulted in impaired neoangiogenesis, leading to a delay in hematopoietic recovery. Conversely, angiopoietin-1 (Ang-1) stimulated hematopoiesis both in wild-type and thrombopoietin-deficient mice. In addition, Ang-1 shortened the duration of chemotherapy-induced neutropenia in wild-type mice. Exogenous VEGF-A and Ang-1 stimulated Tie2 expression in the BM vasculature. These data suggest that VEGF-A-induced up-regulation of Tie2 expression on the regenerating vasculature after BM suppression supports the assembly of sinusoidal endothelial cells, thereby promoting reconstitution of hematopoiesis. Angiopoietins may be clinically useful to accelerate hemangiogenic recovery after myelosuppression.
authors.affiliation: Department of Genetic Medicine and Division of Hematology-Oncology, Weill Medical College of Cornell University, 1300 York Ave, Room D601, New York, NY 10021, USA.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Scott T
authors.initials: ST
authors.lastname: Avecilla
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Shmelkov
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ramos
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000502:physiology; D000818:Animals; D001853:Bone Marrow / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction; D034061:Thrombopoiesis / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D005472:Fluorouracil