Mismatch between oxygen delivery and consumption in the cerebral watershed during subacute global hypoperfusion.

Hemodynamically significant carotid artery stenosis is a common clinical condition that can lead to chronic cerebral hypoperfusion. Despite the well-recognized pivotal role of pial collaterals in maintaining cerebral perfusion during focal arterial occlusions, regulation of microvascular blood flow and oxygenation in the cerebral watershed "pial-collateral territory" during chronic hypoperfusion remains unexplored. To answer this question, we applied 2-photon microscopy and Doppler optical coherence tomography to assess the changes in cerebral blood flow, capillary red-blood-cell (RBC) flux, and intravascular oxygen partial pressure (PO2), seven days after bilateral common-carotid artery stenosis (BCAS). The measurements were performed in the middle-cerebral-artery (MCA) territory and the watershed between the MCA and anterior-cerebral-artery territories in the awake, head-restrained C57BL/6 mice, through a glass-sealed cranial window. The results showed that BCAS induced a significant decrease in microvascular perfusion in the watershed area compared to the MCA territory, with the largest RBC flux reduction observed in the subcortical white matter. The watershed area exhibited a larger drop between arterial and venous PO2 and the calculated oxygen saturation, indicating a significant increase in oxygen extraction fraction following BCAS. Structural analysis of the microvasculature showed significant BCAS-induced dilation of pial collaterals, suggesting a potential compensatory mechanism to improve blood flow in the hypoperfused watershed. However, microvascular morphology did not change in either region, implying an absence of structural remodeling at this early stage. Collectively, these findings point to an oxygen supply-consumption mismatch and heightened vulnerability in the watershed areas, particularly affecting the subcortical white matter, during flow-limiting cervical artery stenosis.