The vascular form of
Ehlers-Danlos syndrome (vEDS), a
rare disease with grave complications resulting from
rupture of major arteries, is caused by mutations of
collagen type III [α1 chain of
collagen type III (COL3A1)]. The only, recently proven, preventive strategy consists of the reduction of arterial wall stress by β-
adrenergic blockers. The heterozygous (HT) Col3a1 knockout mouse has reduced expression of
collagen III and recapitulates features of a mild presentation of the disease. The objective of this study was to determine whether changing the balance between synthesis and degradation of
collagen by chronic treatment with
doxycycline, a nonspecific
matrix metalloproteinase (
MMP) inhibitor, could prevent the development of vascular pathology in HT mice. After 3 months of treatment with
doxycycline or placebo, 9-month-old HT or wild-type (WT) mice were subjected to surgical stressing of the aorta. A 3-fold increase in stress-induced aortic lesions found in untreated HT mice 1 week after intervention (cumulative score 4.5 ± 0.87 versus 1.3 ± 0.34 in WT, p < 0.001) was fully prevented in the
doxycycline-treated group (1.1 ± 0.56, p < 0.001). Untreated HT mice showed increased MMP-9 activity in the carotid artery and decreased
collagen content in the aorta; however, in
doxycycline-treated animals there was normalization to the levels observed in WT mice.
Doxycycline treatment inhibits the activity of tissue
MMP and attenuates the decrease in the
collagen content in aortas of mice haploinsufficient for
collagen III, as well as prevents the development of stress-induced vessel pathology. The results suggest that
doxycycline merits clinical testing as a treatment for vEDS.