This Program Project application, entitled """"""""Molecular and Cellular Mechanisms of Vascular Anomalies"""""""" requests continued funding for collaborative efforts of three research groups, two in Boston, and one in Brussels, Belgium to elucidate pathogenetic mechanisms of human vascular anomalies, to generate mouse models and identify therapeutic targets. These common vascular disorders belong to the group of childhood conditions popularly known as vascular birthmarks. One in about 100 children born have a vascular birthmark, and although significant progress has been made in identifying the genetic basis for many of the more rare forms of these anomalies, they are frequently misdiagnosed and effective therapies are unavailable. To advance pathogenetic understanding of vascular anomalies, provide the basis for better molecular diagnostic tools and development of new rational therapies, the investigators propose to continue their research on infantile hemangioma, a vascular tumor found in 10% of Caucasian children at 1 year of age, and venous malformations through highly interactive program consisting of three Projects and three Cores. Hemangiomas usually appear a few days after birth, grow rapidly for a few weeks to months, and then slowly regress over a 5-10-year period. Malformations do not regress, but grow with the child and can become life-threatening. Building on discoveries made during the first grant period and taking advantage of exceptional patient-data, tissue, cell and nucleic acid resources that have been collected in two Cores, one in Boston and one in Brussels, the investigators propose to use genetic, cell biological, and protein chemistry techniques to gain deeper understanding of how gene mutations that are associated with hemangioma and venous malformations affect endothelial and smooth muscle cell differentiation and function. Animal models comprising human cells transplanted into immunocompromised mice and genetically modified mice carrying hemangioma- and venous malformation-associated mutations will be characterized and used for testing hypotheses and explored for preclinical trials of disease-modifying drugs.

Public Health Relevance

Aimed at developing effective therapies for relatively common vascular disorders of childhood, the results of the proposed research is likely to have significant impact also on other diseases of adults that involve abnormal blood vessel formation, such as growth of malignant tumors, diabetic vascular disease, and agerelated macular degeneration.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-EHB-F (M1))
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Dentistry
United States
Zip Code
Hu, Kai; Olsen, Bjorn R; Besschetnova, Tatiana Y (2017) Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts. Matrix Biol 62:105-114
Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron et al. (2016) Inhibition of Hif1? 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 52-54:127-140
Couto, Javier A; Huang, Lan; Vivero, Matthew P et al. (2016) Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plast Reconstr Surg 137:77e-82e
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
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
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
Limaye, Nisha; Kangas, Jaakko; Mendola, Antonella et al. (2015) Somatic Activating PIK3CA Mutations Cause Venous Malformation. Am J Hum Genet 97:914-21
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
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

Showing the most recent 10 out of 53 publications