[Show abstract][Hide abstract] ABSTRACT: The vascular form of the Ehlers–Danlos syndrome (vEDS) is a rare inherited connective tissue disorder. Patients have a reduced
life span (under 50) due to spontaneous and often fatal rupture of blood vessels and hollow organs. Until very recently no
evidence-based treatment had been available. 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. A mouse model of
vEDS created by inactivation of the Col3a1 gene has been of limited use as only 5% of homozygous animals survived to adulthood. The haploinsufficiency for one COL3A1 allele is one of the genotypes resulting in vEDS. In this review we provide evidence that haploinsufficiency for Col3a1 in mice recapitulates features of vEDS in humans and might be used as an experimental model. There was a reduced level of
aortic collagen and correspondingly reduced aortic wall strength. A spectrum of lesions was detected in the aorta similar
to those observed in human patients. Lesions increased in number and age and were more common in male than in female mice.
Furthermore, potential treatment strategies are discussed including the already tested β-adrenergic receptor (AR)-blocker
therapy, the inhibition of extracellular matrix degrading enzymes, and the only causative approach of selective silencing
of the mutant form of COL3A1 by allele-specific RNA interference.
KeywordsAorta-Aortic wall strength-Beta-blocker therapy-Collagen-Connective tissue-Ehlers–Danlos syndrome-Extracellular matrix-MMP inhibition-Treatment strategies
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Pharmacology and Experimental Therapeutics 03/2011; 337(3):621-7. DOI:10.1124/jpet.110.177782 · 3.97 Impact Factor
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