Tie2 activation contributes to hemangiogenic regeneration after myelosuppression

• Published in: Blood Vol. 106; no. 2; pp. 505 - 513
• Main Authors: Kopp, Hans-Georg, Avecilla, Scott T., Hooper, Andrea T., Shmelkov, Sergey V., Ramos, Carlos A., Zhang, Fan, Rafii, Shahin
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.07.2005; The Americain Society of Hematology; The American Society of Hematology
• Subjects: Angiopoietin-1 - genetics; Angiopoietin-1 - physiology; Animals; Biological and medical sciences; Bone Marrow - blood supply; Bone Marrow - drug effects; Bone Marrow - physiology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Enzyme Activation; Female; Fluorouracil - pharmacology; Fundamental and applied biological sciences. Psychology; Hematopoiesis; Hematopoiesis - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular and cellular biology; Neovascularization, Physiologic; Receptor, TIE-2 - antagonists & inhibitors; Receptor, TIE-2 - genetics; Receptor, TIE-2 - physiology; Regeneration - physiology; Signal Transduction; Thrombopoiesis - drug effects; Thrombopoiesis - physiology; Vascular Endothelial Growth Factor A - physiology; Animal model; Endothelial cell; Angiopoietin 1; Rodentia; Radiotherapy; Tie2 receptor; Angiogenesis; Regeneration; Vertebrata; Chemotherapy; Mammalia; Vascular endothelium growth factor; Mouse; Hematopoiesis; Animal; Secondary effect; Bone marrow; Myelosuppression; Neovascularization
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-11-4269

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.