Chronic Treatment with a Broad-Spectrum Metalloproteinase Inhibitor, Doxycycline, Prevents the Development of Spontaneous Aortic Lesions in a Mouse Model of Vascular Ehlers-Danlos Syndrome

Abstract

There is no proven therapy or prevention for vascular EhlersDanlos syndrome (vEDS), a genetic disorder associated with the mutation of procollagen type III and characterized by increased fragility of vascular and hollow organ walls. Heterozygous COL3A1-deficient (HT) mice recapitulate a mild presentation of one of the variants of vEDS: haploinsufficiency for collagen III. Adult HT mice are characterized by increased metalloproteinase (MMP) activity, reduced collagen content in the arterial walls, and spontaneous development of various severity lesions in aorta. We hypothesized that chronic treatment with a MMP inhibitor would increase collagen content and prevent the development of spontaneous aortic lesions. HT mice were treated since weaning with the broad-spectrum MMP inhibitor doxycycline added to food. At the age of 9 months MMP-9 expression was twice as high in the tunica media of aorta in untreated HT mice, whereas total collagen content was 30% lower (p Ͻ 0.01) and the cumulative score of aortic lesions was eight times higher than in wild-type (WT) mice (p Ͻ 0.01). After 9 months of doxycycline treatment, MMP-9 activity, collagen content, and lesions in the aortas of HT mice were at the level of those of WT mice (p Ͼ 0.05). In the mouse model of collagen III haploinsufficiency treatment with broad-spectrum MMP inhibitor that was started early in life normalized increased MMP activity, reduced aortic collagen content in adults, and prevented the development of spontaneous aortic lesions. Our findings provide experimental justification for the clinical evaluation of the benefit of doxycycline at least in the haploinsufficient variety of vEDS.

Age-associated pro-inflammatory remodeling and functional phenotype in the heart and large arteries

“…Interestingly, aging increases MMP-2-cleaved elastin and activated TGF-β1/TGF-β receptor type II signaling, contributes to increased production of collagen I, II, III, and the biologic glue, fibronectin, and leads to elastin fragmentation and fibrosis [ 146 , 147 ]. In addition to increases in MMP-2 activity, activation of the intracellular calcium-dependent proteinase, calpain-1, is also involved in TGF-β1 activation and increased collagen production in old VSMCs [ 146 ] .…”

Matrix Metalloproteinases Promote Arterial Remodeling in Aging, Hypertension, and Atherosclerosis

“…MMPs, downstream molecules of both Ang II and TGF-β (for reviews) 1, 2 , play causal roles in the development of the aortic aneurysm 59, 68, 69 . MMP-2/-9 activation is able to erode the arterial wall, a histological foundation of the aortic aneurysm development 59, 68 . Further, MMP-2/-9 activation signaling also promotes a loss of VSMCs and facilitates aortic dilation 70 .…”

“…Cathepsin S deficiency decreases MMP-2 activation and retards the pathogenesis of aneurysm 73 . Chronic treatment with a broad-spectrum MMP inhibitor, doxycycline, prevents the development of spontaneous aortic aneurysm lesions 68 .…”

“…The pathophysiological vascular, cellular and molecular events of aging, hypertension, atherosclerosis, and their complications are recapitulated in experimental animals with over-activation of MMPs (Table). In contrast, MMP inhibition attenuates age-associated pathophysiologic arterial remodeling in animal models of hypertension and atherosclerosis 4–8, 68 . Thus, appreciation of the MMP involvement in arterial wall aging and age-associated arterial diseases and the ability to detect its involvement in arterial wall inflammation, vulnerable plaques and the progression of aneurysm/dissection will impact on future translational research to delay arterial remodeling that accompanies aging and its participation in these age-associated arterial diseases.…”

Angiotensin II Promotes Thoracic Aortic Dissections and Ruptures in Col3a1 Haploinsufficient Mice

“…13,14 Because the vascular features of these mice do not recapitulate the human disease, we, therefore, decided to induce experimentally vascular dissections or ruptures in young adults Col3a1 +/− and Col3a1 +/+ BALB/c mice, to investigate whether Col3a1 +/− mice are more susceptible to vascular ruptures than wild-type mice as observed in vEDS patients. Among the different experimental methods developed to study the formation and progression of vascular disease, the chronic infusion of angiotensin II (AngII) has consistently been used as a model of aortic dissections and arterial ruptures notably in hypercholesterolemic mice.…”