Germline activation of H-RAS oncogenes is the primary cause of Costello syndrome 
(CS), a neuro-cardio-facio-cutaneous developmental syndrome. Here we describe 
the generation of a mouse model of CS by introduction of an oncogenic Gly12Val 
mutation in the mouse H-Ras locus using homologous recombination in ES cells. 
Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, 
resulted in hyperplasia of the mammary gland. However, development of tumors in 
these mice was rare. H-RasG12V mutant mice closely phenocopied some of the 
abnormalities observed in patients with CS, including facial dysmorphia and 
cardiomyopathies. These mice also displayed alterations in the homeostasis of 
the cardiovascular system, including development of systemic hypertension, 
extensive vascular remodeling, and fibrosis in both the heart and the kidneys. 
This phenotype was age dependent and was a consequence of the abnormal 
upregulation of the renin-Ang II system. Treatment with captopril, an inhibitor 
of Ang II biosynthesis, prevented development of the hypertension condition, 
vascular remodeling, and heart and kidney fibrosis. In addition, it partially 
alleviated the observed cardiomyopathies. These mice should help in elucidating 
the etiology of CS symptoms, identifying additional defects, and evaluating 
potential therapeutic strategies.