Lack of collagen XV is protective after ischemic stroke in mice

Collagens are key structural components of basement membranes, providing a scaffold for other components or adhering cells. Collagens and collagen-derived active fragments contribute to biological activities such as cell growth, differentiation and migration. Here, we report that collagen XV knock-out (ColXV KO) mice are resistant to experimental ischemic stroke. Interestingly, the infarcts of ColXV KO mice were as small as those of wild-type (WT) mice thrombolysed with recombinant tissue plasminogen activator (rtPA), the actual treatment for ischemic stroke. Importantly, there were no differences in the architecture of cerebrovascular anatomy between WT and ColXV KO mice. We found a twofold increase of the most potent pro-angiogenic factor, type A vascular growth endothelial factor (VEGF-A) in the ipsilateral cortex of rtPA-treated ischemic WT mice compared with untreated ischemic and sham-operated counterparts. A similar increase of VEGF-A was also found in both rtPA and untreated ischemic ColXV KO mice compared with sham ColXV KO mice. Finally, we evidenced that the levels of ColXV were increased in the plasma of WT mice treated with rtPA compared with untreated ischemic counterparts. Altogether, this study indicates that the lack ColXV is protective after stroke and that the degradation of endothelial ColXV may contribute to the beneficial effect of rtPA after ischemic stroke. The neuroprotection observed in ColXV KO mice may be attributed to the increased VEGF-A production following stroke in the ischemic territory. Stroke is a leading cause of death and long-term disability worldwide.1 Ischemic strokes represent 80% of cerebral strokes and result from the obstruction of a major cerebral artery by a thrombus or an embolus which reduces the blood flow in downstream targeted brain regions, leading to brain damage. The establishment of the primary ischemic lesion is followed by a series of secondary events that worsens tissue damage, including vascular, cellular and molecular events.2 Nowadays, the only treatment for ischemic stroke is reperfusion with intravenous administration of recombinant tissue plasminogen activator (rtPA; Alteplase) within a strict time frame up to 4.5 h, leading to an improved functional recovery and reduced neurological deficits.3 Additionally to its narrowed therapeutic window, rtPA also increases the risk of intracerebral hemorrhagic transformations and is not efficient at degrading platelet-rich thrombi. Taking together all the limitations for the use of rtPA, only 5% of ischemic stroke patients are eligible for rtPA-induced thrombolysis.4 Therefore, it is essential to better understand stroke pathophysiology in order to find safer and more efficient approaches for therapy. Collagens are well-known to be critical extracellular components in vascular stability and functions. Some collagens such as ColXV, ColXVIII and ColXIX have also been shown to be essential for motor axon guidance and neuromuscular development.5, 6, 7 The structurally homologous ColXV and ColXVIII constitute the so called multiplexin family of non-fibrillar collagens, characterized by multiple triple helix interruptions and similar non-collagenous sequences.8 Nevertheless, they differ in their functional properties and expression patterns and for example, contrary to ColXVIII, ColXV predominantly carries chondroitin sulfate chains and was therefore classified as a chondroitin sulfate proteoglycan (CSPG).9 It is mainly produced by skeletal and cardiac muscle, and endothelial cells, occurring at the basement membranes adjacent to these cells. ColXV knock-out (KO) mice suffer from mild skeletal and cardiac myopathy10, 11 and defective myelination of peripheral nerves.12 In this study, we report for the first time the neuroprotective effect of ColXV deficiency in mice suffering from ischemic stroke. Accordingly, we found an increase of type A vascular endothelial growth factor (VEGF-A) in the ischemic cortex of ColXV KO mice. Additionally, we showed that rtPA increased the presence of unbound ColXV in the plasma of wild-type (WT) mice after stroke.
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