The vascular form of Ehlers-Danlos syndrome (VEDS) results from mutations in the COL3A1 gene that encodes the chains of collagen type III and alters the sequence in the triple-helical domain. Complications in afflicted patients include spontaneous and often fatal rupture of blood vessels and hollow organs, particularly the colon. The haploinsufficiency for one COL3A1 allele is one of the genotypes resulting in VEDS. Homozygous Col3a1 mice (-/-), the only currently reported mouse model of VEDS, cannot be used for experiments due to extremely high prenatal mortality. We hypothesized, that heterozygous (-/+) Col3a1 mice, originally described as phenotypically normal, could develop characteristic pathology in the older age and thus also serve as an experimental model of haploinsufficiency. To test this hypothesis we conducted histological evaluation of aortas of 9, 14 and 21 months old (+/­) and (+/+) Col3a1 mice. Mason trichrome staining revealed different structural abnormalities in the aortas of 100% of (-/+) male and 50% of (-/+) female mice of all ages, while no pathology was found among wild type female and very small number among wild type male mice. Pathology consisted of intima interruption, elastin fragmentation, spindle cell proliferation, inflammation, and reactive fibrosis. Therefore, the older (-/+) COL3A1 mice can be used as an experimental model of collagen III haploinsufficiency. We further hypothesized that treatment with broad spectrum MMP inhibitor, doxycycline would prevent or attenuate the development of aortic lesions in (-/+) COL3A1 mice. Six months old females (-/+) and wild type mice were treated for 3 months with the broad spectrum MMP inhibitor doxycycline (25 mg/kg per day). At the end of the treatment, under general inhalation narcosis (2% of isoflurane in oxygen) the aortas were surgically stressed: for 30 sec the blood flow was stopped by pressing the q-tip at the level of renal arteries to elevate the blood pressure above stoppage. One week after intervention aortas were harvested and processed. The number of lesions was counted in serial sections every 2 mm across aortas. The average number of lesion in untreated wild type mice was 0.90.32. In untreated (-/+) mice the average number of lesions was elevated to 2.30.40 (p<0.05); the average number of lesion in (-/+) mice treated with doxycycline was 1.10.50 - significantly (p<0.05) lower than in untreated animals and similar to wild type mice. Result suggests that doxycycline merits clinical testing as a treatment for VEDS.