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
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
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
Dellinger, Michael T; Garg, Nupur; Olsen, Bjorn R (2014) Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone 63:47-52
Uebelhoer, Melanie; Natynki, Marjut; Kangas, Jaakko et al. (2013) Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum Mol Genet 22:3438-48
Amyere, Mustapha; Aerts, Virginie; Brouillard, Pascal et al. (2013) Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet 92:188-96
Butler, Matthew G; Dagenais, Susan L; Garcia-Perez, Jose L et al. (2012) Microcephaly, intellectual impairment, bilateral vesicoureteral reflux, distichiasis, and glomuvenous malformations associated with a 16q24.3 contiguous gene deletion and a Glomulin mutation. Am J Med Genet A 158A:839-49
Greenberger, Shoshana; Yuan, Siming; Walsh, Logan A et al. (2011) Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J Invest Dermatol 131:2467-76
Goujon, Elisa; Cordoro, Kelly M; Barat, Muriel et al. (2011) Congenital plaque-type glomuvenous malformations associated with fetal pleural effusion and ascites. Pediatr Dermatol 28:528-31
Boon, Laurence M; Ballieux, Fanny; Vikkula, Miikka (2011) Pathogenesis of vascular anomalies. Clin Plast Surg 38:7-19
Bowen, Margot E; Boyden, Eric D; Holm, Ingrid A et al. (2011) Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet 7:e1002050

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