Microcirculation Dysfunction in Subacute Stroke: The Role of Delayed Capillary Pericyte Loss

Area of Science:

• Neuroscience
• Vascular Biology
• Stroke Research

Background:

• Post-recanalization microcirculation dysfunction is a major cause of poor outcomes in ischemic stroke.
• Pericytes are implicated in early microcirculation dysfunction, but their long-term fate and contribution to sustained dysfunction are unclear.

Purpose of the Study:

• To investigate the long-term fate and function of pericytes after ischemic stroke.
• To identify imaging features associated with capillary perfusion.
• To evaluate therapeutic strategies targeting pericyte dysfunction and survival.

Main Methods:

• Longitudinal two-photon imaging in PDGFRβ-tdTomato mice subjected to transient middle cerebral artery occlusion (tMCAO) over 14 days.
• Multivariate analysis for imaging features linked to capillary perfusion.
• Assessment of pericyte death via immunohistochemistry and Western blot.
• Administration of fasudil and necrostatin-1 to modulate pericyte function and survival.

Main Results:

• Pericyte loss by day 7 post-stroke correlated with impaired microcirculation perfusion.
• Fasudil alone improved perfusion acutely but not long-term; it did not alter pericyte fate.
• Necroptosis contributed to delayed pericyte loss; combined fasudil and necrostatin-1 prevented loss and improved outcomes by day 14.

Conclusions:

• Delayed pericyte loss contributes to irreversible microcirculation dysfunction in the subacute phase of stroke.
• Targeting pericyte dysfunction and necroptosis is a promising therapeutic strategy for stroke recovery.