The Edpm5 locus prevents the 'angiogenic switch' in an estrogen-induced rat pituitary tumor

Edpm5 is one member of a group of quantitative trait loci that are responsible for the difference in susceptibility to estrogen-induced prolactinoma between the Fischer 344 (F344) and Brown Norway (BN) strains. Upon chronic estrogen treatment F344 rats develop large, hemorrhagic and invasive pituitary tumors, which exhibit both tumor angiogenesis and neoplasia. In contrast, BN rats do not develop a tumor despite an estrogen-induced increase in lactotroph density. To investigate the role of Edpm5 in the development of these tumors, we have generated a novel congenic rat strain F344.BN-Edpm5BN by introgressing the segment of rat chromosome bearing Edpm5 from BN into the F344 strain background. Phenotypic differences between F344 and F344.BN-Edpm5BN must be due to a gene(s) within the chromosomal interval encompassing Edpm5. Through use of these strains, we find that Edpm5 specifically regulates the switch to angiogenic phenotype, independent of neoplasia. The F344.BN-Edpm5BN rats developed tumors, which exhibited significant growth, 7-fold greater mass than the pituitary of untreated rats, and neoplasia indistinguishable from that of the F344 strain. However, the F344.BN-Edpm5BN rat tumor had a non-angiogenic phenotype. After chronic estrogen treatment, there was no increase in microvessel count over untreated controls in F344.BN-Edpm5BN tumors, whereas F344 rat tumors showed a significant increase (P < 0.0005). The ultrastructural morphology of the pituitary blood vessels also did not show significant angiogenesis associated changes in F344.BN-Edpm5BN rat pituitary tumors. In contrast the parental strain F344 had pronounced angiogenic activity. The F344.BN-Edpm5BN strain also fails to express VEGF at the high levels seen in the F344 rat pituitary after estrogen treatment. Hence at least one gene that has a large impact, directly or indirectly, on the switch to angiogenic phenotype must reside within the chromosomal interval that is the Edpm5 quantitative trait locus.