Dll4- and Sox17-mediated vascular integrity in the central nervous system

Abstract

Part I. Although hypertension is a well-known risk factor of brain diseases associated with blood-brain barrier (BBB) disruption, the location and pathophysiology of hypertension-induced BBB disruption remain unknown. We found that an endothelial transcription factor Sox17 protects BBB in the thalamus, one of the areas most frequently affected by hypertensive intracerebral hemorrhage, against hypertension. Sox17 deficiency promoted hypertension-driven non-hemorrhagic leakage in the thalamus via destabilized tight junctions and increased transcytosis, leading to increased theta brainwave activity. Prolonged hypertension induced cerebral microbleeds in the thalamus. Interestingly, hypertension upregulated p16INK4a, a cardinal senescence player, in Sox17-deficient vessels and p16ink4a co-deletion suppressed vascular leakage and microhemorrhage. Importantly, incidence of cerebral IgG leakage and microbleeds was higher in hypertension patients with low Sox17 levels than ones with normal Sox17 levels, implicating low Sox17 expression in hypertensive BBB disruption. Together, Sox17 deficiency promotes hypertension-induced non-hemorrhagic leakage impairing brain function and subsequent cerebral microbleeds via premature endothelial senescence.

Part II. Blood-brain barrier (BBB) disruption is known to contribute in the pathogenesis of many diseases of the central nervous system (CNS). Consequently, restoration of BBB integrity may affect the onset or course of CNS diseases associated with BBB breakdown. Therefore, identifying novel therapeutic targets for BBB stabilization may be beneficial. We found that Dll4 is essential for BBB and blood-spinal cord barrier (BSCB) integrity. CNS endothelial cell-specific Dll4 deletion leads to blood-CNS barrier breakdown, neurologic deficits as ataxia, hindlimb paralysis with histologic evidence of neuroinflammation and demyelination. We also discovered that Dll4 repression is seen in pathological states such as EAE and enhanced Dll4/Notch signaling ameliorates EAE course and neurologic symptoms. Dll4 signaling in CNS endothelial cells may be a therapeutic target for CNS diseases with BBB disruption-induced neuroinflammation.