Global hypoperfusion leads to a mismatch in oxygen delivery and consumption in the cerebral watershed area.

Despite the pivotal role of pial collaterals in maintaining cerebral blood flow during focal brain ischemia, it is largely unexplored how the microvascular blood flow and oxygenation in the watershed "pial-collateral territory" differ from those in the territory supplied by the major arteries during chronic global hypoperfusion. To answer this question, we applied 2-photon microscopy and Doppler optical coherence tomography to investigate the changes in cerebral microvascular blood flow and partial pressure of oxygen (PO 2 ), induced by bilateral common carotid artery stenosis (BCAS). The measurements were performed in the somatosensory cortex that is supplied by the middle cerebral artery (MCA), and in the adjacent watershed area in the awake, head-restrained C57BL/6 mice, via the chronic cranial window. The results showed that the BCAS induced a larger decrease in capillary red blood cell (RBC) flux in the watershed area than in the MCA territory, especially in the subcortical white matter. Besides, PO 2 in the pial collaterals was significantly lower than that in the upstream MCA segments under control conditions. However, the PO 2 changes in the arteries and veins under global hypoperfusion displayed different trends in the two interrogated regions, resulting in a significant increase in oxygen extraction fraction in the watershed area. These findings suggest a mismatch between oxygen supply and demand in the watershed area due to global hypoperfusion and increased subcortical white matter vulnerability. We have also observed dilation of the pial collaterals after BCAS, which might suggest a compensatory mechanism to improve the blood flow in the watershed under hypoperfusion.