Cerebral stroke leads to long-term disability, yet post-stroke treatment remains primarily limited to rehabilitation. The partial functional recovery that does occur is due in part to neurovascular plasticity of the brain region adjacent to stroke damage?the peri-stroke penumbra. However, attempts to manipulate the neurovasculature post-stroke by promoting angiogenesis?sprouting of new capillary vessels?have not been successful, in part because angiogenesis can lead to tortuous, leaky vessels that do not increase blood flow. Alternatively, arteriogenesis?the generation of large-bore vessels in response to shear stress?could play an important role in post-stroke recovery and represent a novel therapeutic target. However, the lack of tools to specifically manipulate arteriogenesis has hampered efforts to test this hypothesis. We identified Dach1 as an endothelial transcription factor as a tool to specifically drive arteriogenesis. Here, we will use new mouse models that allow us to bi-directionally control Dach1 levels in endothelial cells, to determine to what extent arteriogenesis is involved in post-stroke recovery of brain functions. Specifically, we will examine the links between arteriogenesis and post-stroke recovery of the vascular network (Aim 1), neurovascular coupling (Aim 2), and behavior (Aim 3). Our long-term goal is to understand the mechanisms of adaptive post-stroke neurovascular plasticity to develop new treatments and improve brain health. Funding of this proposal will enable an unbiased study of the brain following stroke with unprecedented temporal and spatial resolution in freely behaving animals, identify the specific role of arteriogenesis in post-stroke recovery, and may unveil new therapeutic targets that enhance the therapeutic window of post-stroke rehabilitation, which is a key limiting factor in treating stroke patients.

Public Health Relevance

Cerebral stroke is a common cause of long-term disability, yet current post-stroke treatments have a very short therapeutic window, impairing post-stroke rehabilitation leading to incomplete recovery. In theory, vascular remodeling should improve blood flow and enable structural and functional recovery from stroke, but previous attempts to accomplish this by increasing angiogenesis (i.e. growth of new capillary vessels) have been unsuccessful. Here, we propose to overcome this limitation by specifically inducing arteriogenesis (i.e. expansion of existing arterioles into large arteries) after stroke, which has higher potential to expand the time window for treating patients with stroke because it is more likely to facilitate bulk blood flow to the ischemic area.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Koenig, James I
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J. David Gladstone Institutes
San Francisco
United States
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