Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents
Boyeon Lee, … , Sarah A. Thomas, Gregory J. Bix
Boyeon Lee, … , Sarah A. Thomas, Gregory J. Bix
Published July 11, 2011
Citation Information: J Clin Invest. 2011;121(8):3005-3023. https://doi.org/10.1172/JCI46358.
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Research Article Angiogenesis

Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

Abstract

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5β1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment.

Authors

Boyeon Lee, Douglas Clarke, Abraham Al Ahmad, Michael Kahle, Christi Parham, Lisa Auckland, Courtney Shaw, Mehmet Fidanboylu, Anthony Wayne Orr, Omolara Ogunshola, Andrzej Fertala, Sarah A. Thomas, Gregory J. Bix

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Figure 1

Perlecan DV is upregulated after stroke in rodents.

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Perlecan DV is upregulated after stroke in rodents. (A) Anti-DV Western ...
(A) Anti-DV Western blot analysis of post-stroke rat brain, with GAPDH internal loading control. DV levels were assessed in both ipsilateral (stroke) and contralateral hemispheres on the post-stroke days as labeled. GAPDH loading control lanes on contralateral PSD 5 and 7 were run on the same gel but were noncontiguous. (B) Densitometry analysis of DV Western blot as shown in A. DV band density intensities were normalized to their respective GAPDH bands (**P < 0.01 between ipsi- and contralateral hemispheres for each PSD, n = 15 per PSD). (C) DV and CD31 co-immunohistochemistry of rat stroke and corresponding contralateral brain tissue on PSD 3 and 7. Scale bar: 50 μM. (D) Anti-DV Western blot analysis of PSD 3 brain tissue from WT littermate mice and Pln–/– mice, with GAPDH as internal loading control. (E) Plot of mean ischemic lesion volumes of stroke WT mice and Pln–/– mice (**P < 0.01 between groups on each PSD, n = 15 per group per PSD). (F) WT or Pln–/– mouse brain TTC staining at PSD 3. Yellow asterisks indicate ischemic lesions (TTC-negative, appears white).