Angiogenesis is essential for normal embryonic development, wound healing, and postischemic tissue repair. However, angiogenesis is also associated with pathological conditions like diabetes, psoriasis, and cancer. The Vascular Endothelial Growth Factors (VEGF) are a family of secreted glycoproteins that control angiogenesis. Recent studies have shown that different strains of inbred mice have a 10-fold range of response to VEGF-induced angiogenesis. Thus, unknown genetic factors must control VEGF responsiveness in mice. The discovery of the genes behind these differences could lead to new angiogenic therapies. We have developed a novel quantitative ex-vivo skin biopsy method to evaluate angiogenic response in the skin of mice. Our method is unique for the following reasons: First, the microvasculature of the skin is well-suited for angiogenic response because it is a primary site of neovascularization in wounding and the skin is a common site of tumor formation. Second, our skin-based approach is performed on multiple samples per individual, decreasing the potential for environmental variation. Finally, because our method is performed on euthanized three-day-old mice, we can perform mapping crosses in an efficient manner. Our preliminary findings have shown that FVB/NJ mice produced the highest amount of blood vessels in our skin biopsy model when compared to C57BL/6J mice. The VEGF hypersensitivity in FVB mice is a recessive trait and based on our preliminary data is likely to be controlled by fewer QTLs than previous approaches designed to map angiogenesis QTLs in mice. We propose to map the QTLs responsible for the novel difference in FVB/NJ skin and define the biological basis of these differences. This work is vital to human health because several therapies designed to control angiogenesis in human disorders are currently in clinical trials based in part on data obtained from mouse models. Our results will improve the validity of testing of mouse models and could lead to the discovery of new therapeutic targets or biomarkers for VEGF mediated therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR054828-02S2
Application #
7847307
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2009-06-10
Project End
2010-08-31
Budget Start
2009-06-10
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$16,340
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
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Kadiyala, Sridhar B; Papandrea, Dominick; Tuz, Karina et al. (2015) Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity. Epilepsy Res 109:183-96
Kadiyala, Sridhar B; Papandrea, Dominick; Herron, Bruce J et al. (2014) Segregation of seizure traits in C57 black mouse substrains using the repeated-flurothyl model. PLoS One 9:e90506
Cole, Richard; Hoffman, Timothy; Smith, Jason et al. (2013) Stereotaxic device for optical imaging of mice hind feet. J Biomol Tech 24:128-31
Liu, Fang; Smith, Jason; Zhang, Zhen et al. (2010) Genetic heterogeneity of skin microvasculature. Dev Biol 340:480-9