Molecular and Genetic Analysis of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention
Background—Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases including cerebral microbleeds, porencephaly and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown and there is a lack of effective treatment.
Methods and Results—Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small vessel disease, recurrent hemorrhagic strokes and age-related macro-angiopathy. We showed that allelic heterogeneity, genetic context and environmental factors, such as acute exercise or anticoagulant medication, modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a FDA-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction of ICH severity.
Conclusions—Our data are the first to show therapeutic prevention in vivo of ICH due to Col4a1 mutation, and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations.
- intracerebral hemorrhage
- cerebrovascular disorders
- Received September 22, 2014.
- Revision received January 31, 2015.
- Accepted February 26, 2015.