Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1‐related stroke

Abstract

Mutations in the α1 (COL4A1) or α2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1-related intracerebral haemorrhage and identify a marker for haemorrhage risk stratification. A combination of histological, immunohistochemical, and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease-causing COL4A1 p.G498V mutation. Mutant mice developed cerebral microhaemorrhages and macroscopic haemorrhages (macrohaemorrhages), the latter with reduced penetrance, mimicking the human disease. Microhaemorrhages that occurred in early postnatal life were associated with a transient, generalized increase in blood-brain barrier permeability at the level of capillaries. Macrohaemorrhages, which occurred later in life, originated from deep brain arteries with focal loss of smooth muscle cells. Similar smooth muscle cell loss was detected in retinal arteries, and a time-course analysis of arterial lesions showed that smooth muscle cells are recruited normally in arterial wall during development, but undergo progressive apoptosis-mediated degeneration. By assessing in parallel the extent of these retinal arterial lesions and the presence/absence of macrohaemorrhages, we found that the arterial lesion load in the retina is strongly correlated with the burden of macrohaemorrhages. We conclude that microhaemorrhages and macrohaemorrhages are driven by two distinct mechanisms. Moreover, smooth muscle cell degeneration is a critical factor underlying the partial penetrance of COL4A1-related macrohaemorrhages, and retinal imaging is a promising tool for identifying high-risk patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The pericyte microenvironment during vascular development

“…Taken together with previous studies, it is intriguing to speculate that the hypoxic conditions within several of the aforementioned disease states might not only antagonize pericyte constriction mechanisms but also cause an aberrant increase in the expression of αSMA and other contractile machinery proteins. This “hyper‐muscularization” of pericytes has also been reported in other contexts . This working model requires further studies to determine whether such relationships exist.…”

“…This "hyper-muscularization" of pericytes has also been reported in other contexts. 177 This working model requires further studies to determine whether such relationships exist. In summary, in addition to their potential role in modulating capillary tone, pericytes within the microcirculation contribute to a number of important processes that promote the transition of microvessels from sprouting and remodeling to mature, quiescent networks.…”

Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage

“…129/Sv background as described previously 14,16 . Col4a1 +/G1064D mice on a C57BL/6 background were obtained from GlaxoSmithKline (Brentford, UK).…”

“…Beside sporadic forms of deep ICH, monogenic forms largely indistinguishable from sporadic forms have been characterized offering excellent opportunities for mechanistic studies using genetic models. Heterozygous mutations in the α1 (COL4A1) chain of collagen type IV, which is a major component of vascular basement membranes (BM), are associated with spontaneous deep ICHs in humans or mice in the absence of hypertension, although with incomplete penetrance 14,15 .…”

Use of sodium 4-phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in Col4a1 mutant mice

“…Alternatively, the distinct developmental time course and broad distribution of microbleeds versus larger subcortical hemorrhages in the basal ganglia of Col4a1 mutant mice could account for this discrepancy ( Ratelade et al, 2018 ). Indeed, multifocal microbleeds are typically observed throughout the brains of newborn and juvenile mutant animals and appear to resolve by 3 months of age, whereas the onset of subcortical hemorrhages in the basal ganglia of Col4a1 mutant mice generally occurs in early adulthood and progressively increase with age ( Gould et al, 2005 ; Jeanne et al, 2015 ; Ratelade et al, 2018 ). Thus, it is possible that early cerebral microbleeds detected in 1MO animals are largely cleared by 2MO, while the incidence of subcortical hemorrhage only becomes prominent after 2MO or in response to environmental triggers such as exercise.…”