Infantile hemangiomas are the most common tumors in infancy, typically appearing on head and neck around the second week of life, growing rapidly (proliferating phase) over a few weeks and months, and slowly regressing over 7-10 years (involuting phase). Most hemangiomas are single, small lesions, but some can destroy normal tissue or threaten life. In studies of tissues and endothelial cells from proliferating-phase hemangiomas we have found expression of VEGFR1 to be only 10-20% of that in control endothelial cells and tissues. Low VEGFR1 levels result in VEGF-dependent activation of VEGFR2 and its downstream signaling targets, including genes already known to be abnormally expressed in hemangioma tissue. Addition of soluble VEGFR1 or VEGF antibodies to hemangioma endothelial cells reduces their high VEGFR2 signaling and proliferative activities. We have further shown that low expression of VEGFR1 in hemangioma is caused by reduced activity of an NFAT-controlling complex involving VEGFR2, the integrin- like receptor TEM8 and pi integrin. In three hemangioma patients (of nine studied) heterozygous missense mutations in VEGFR2 or TEM8 provide an explanation for the reduced activity of the VEGFR2/TEM8/pi integrin complex. Future studies aim at generating mice carrying TEM8 and VEGFR2 mutations for studies of the effects of the mutations on angiogenesis and identification of additional components of the VEGFR2/TEM8/pi integrin -containing complex. In collaboration with Project 3 such components will be screened for mutations in hemangiomas where mutations in VEGFR2 or TEM8 have not been found. Based on preliminary studies of pathways that regulate apoptosis in endothelial cells, we also plan studies of involuting hemangiomas aimed at identifying strategies to accelerate involution in clinically problematic tumors. In collaboration with Project 2 transplantation into immunocompromised mice will be used for preclinical testing of disease-modifying drugs and to test the hypothesis that the hemangioma endothelial phenotype can be induced in cells carrying risk factor mutations by localized and sustained activation of VEGFR2.

Public Health Relevance

These studies are anticipated to lead to identification of targets for drugs to effectively treat rapidly growing infantile hemangiomas, the most common tumors of childhood. The work is also likely to have impact on other diseases in adults involving abnormal angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR048564-10
Application #
8528328
Study Section
Special Emphasis Panel (ZAR1-EHB-F)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$433,446
Indirect Cost
$53,507
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron et al. (2016) Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A 113:E338-47
Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R et al. (2016) VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 52-54:127-40
Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin et al. (2015) Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis. Matrix Biol 42:56-73
Smadja, David M; Levy, Marilyne; Huang, Lan et al. (2015) Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost 114:735-47
Huang, Lan; Nakayama, Hironao; Klagsbrun, Michael et al. (2015) Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33:133-45
Limaye, Nisha; Kangas, Jaakko; Mendola, Antonella et al. (2015) Somatic Activating PIK3CA Mutations Cause Venous Malformation. Am J Hum Genet 97:914-21
Nakayama, Hironao; Huang, Lan; Kelly, Ryan P et al. (2015) Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins. Biochem Biophys Res Commun 464:126-32
Boscolo, Elisa; Limaye, Nisha; Huang, Lan et al. (2015) Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest 125:3491-504
Dellinger, Michael T; Garg, Nupur; Olsen, Bjorn R (2014) Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone 63:47-52
Lee, D; Boscolo, E; Durham, J T et al. (2014) Propranolol targets the contractility of infantile haemangioma-derived pericytes. Br J Dermatol 171:1129-37

Showing the most recent 10 out of 50 publications