Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome

Abstract

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects ofCOL3A1mutations that cause vascular Ehlers Danlos Syndrome

“…Our UPR data provide direct evidence that ER stress and UPR activation are a feature of vEDS. This is supported by signs of ER stress in the vasculature of a vEDS mouse model 21 , defects in ER homeostasis on transcriptomic analysis of fibroblasts 33,34 , and a delay in protein folding due to COL3A1 glycine mutations in a bacterial expression system 35 . The detection of ER stress in fibroblasts but limited evidence from smooth muscle cells 20,21 could reflect a cell type-dependent mechanism whereby UPR activation may occur more readily due to the higher expression of ECM proteins in fibroblasts compared to smooth muscle cells (Human Protein Atlas) 36 ; Dataref: Karlsson et al, 2021).…”

“…Recent data from mouse models explored the efficacy of modulating more downstream ERK signalling mechanisms 20 . We set out a complementary approach focusing on more upstream mechanisms that may be applicable to multiple mutations and tissues to help overcome recently observed allele specific outcomes of treatments targeting these further downstream mechanisms [20][21][22] . Excitingly PBA rescued both the ER stress and improved the quality of the secreted collagen without increasing levels of secretion per se, as determined by the susceptibility to trypsin digest.…”

“…This could represent an avenue for rescuing both extra-and intracellular effects and be effective across different COL3A1 mutations and tissues. This would overcome the genotypedependent efficacy of recently proposed strategies that target more downstream mechanisms or blood pressure [20][21][22] . The availability of FDA-approved compounds, including PBA, TUDCA and CBZ, that target protein folding or degradation is particularly interesting as these are well-tolerated with good safety records 29 , and repurposing FDA/EMA-approved compounds is an attractive cost-effective strategy for developing treatments for rare diseases 30 .…”

“…Inhibiting PKC/MEK/ERK signalling (e.g. via cobimetinib), improved survival 20 in some but not all mouse models harbouring Col3a1 mutations 21 . Considering the multi-systemic nature of the disease that affects different cell types, targeting single downstream pathways may only be effective for particular cell types and/or mutations, as found for celiprolol treatment in mice 20,22 .…”

The dysmorphic phenotype in vascular Ehlers Danlos syndrome

“…Collagens are a major constituent of the pial membrane which plays a critical role in lamination and neuronal migration within the fetal brain. Legrand et al (2022) showed that ‘knock-in’ mice had a significant therapeutic response to Losartan, reversed on stopping and worsened by exogenous angiotensin II. Other antihypertensive agents were ineffective.…”