How are structural components of the BBB affected in diseases of the brain and spinal cord, where barrier function is impaired?
With more than 795,000 new cases every year, stroke is the fifth leading cause of mortality and the first leading cause of long-term disability in the U.S. More than 85% of all strokes are ischemic, caused by the occlusion of one of the arteries supplying blood to the brain.
We have shown that in a murine model of ischemic stroke (transient middle cerebral artery occlusion – tMCAo), stroke-induced BBB breakdown appears as two distinct waves of increased vascular permeability: the first one, occurring between 6 and 12 hours after reperfusion, caused by increased rates of transcytosis, and the second one, starting from 24 hours after reperfusion. We have also shown in mice that elimination of Caveolin-1 (Cav1-/-), a protein essential for the transcellular transport through caveolae, can effectively rescue the first wave of increased BBB permeability without affecting degradation of AJ and TJs, indicating that the two processes are mechanistically independent.
Despite the huge medical need, thrombolytic treatment with tPA remains the only FDA-approved therapy for ischemic stroke. However not every patient is eligible for tPA treatment, since it increases the risk for intracerebral hemorrhage (ICH), an event recognized as secondary due to BBB breakdown. tPA has also been shown to exacerbate BBB damage during stroke intervention.
Research in our laboratory aims at exploring the mechanisms of BBB dysfunction during stroke pathogenesis in order to identify potential novel candidates for targeted therapies able to restore BBB functionality after ischemic stroke and reperfusion, with the ultimate objective of addressing the safety concerns arising from reperfusion injury.
- Song S, Huang H, Guan X, Fiesler V, Bhuiyan MIH, Liu R, Jalali S, Hasan MN, Tai AK, Chattopadhyay A, Chaparala S, Sun M, Stolz DB, He P, Agalliu D, Sun D, Begum G. (2021) Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke. Prog Neurobiol Apr;199:101963.
- Miller EC, Sundheim KM, Willey JZ, Boehme AK, Agalliu D, Marshall RS. (2018) The Impact of Pregnancy on Hemorrhagic Stroke in Young Women. Cerebrovasc Dis 2018;46(1-2):10-15.
- Knowland D., Arac A., Sekiguchi K.J., Hsu M., Lutz S.E., Perrino J., Steinberg G.K., Barres B.A., Nimmerjahn A., and Agalliu D (2014). Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82(3):603-617.
- Liu S, Agalliu D, Yu C, Fisher M (2012). The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des 18(25):3653-62.
Mechanisms of BBB dysfunction and repair after ischemic stroke.
Dysregulated BBB permeability is a key feature of the pathology of ischemic stroke. We have previously shown that BBB disruption occurs in two distinct waves: an early phase driven by an increase in transcytosis (transcellular permeability), and a later phase due to endothelial junctions dismantling (paracellular permeability). While we can successful prevent the first wave by inhibiting transcellular transport in the animal model (Caveolin-1 knock-out), we are still investigating the molecular mechanisms that regulate paracellular permeability with the ultimate goal to rescue the second wave of BBB dysruption. In particular, we are focusing and the role of Rab7, a small GTPase involved in the endocytic pathway by potentially directing endothelial junctional proteins to lysosomal degradation after stroke.
We are also interested in understanding the impact that sensory stimulation has on BBB function after ischemic stroke. Sensory stimulation in animal models of ischemic stroke has been repeatedly shown to reduce the stroke volume and to ameliorate the neurological manifestations, supposedly by providing an emergency supply of blood flow through collateral circulation. However, the translation of sensory stimulation in the human pathology has proven to be ineffective, or even deleterious. Together with a network of other European and US laboratories, we are investigating the molecular mechanisms activated by sensory stimulation, particularly at the level of the BBB, with the aim of identifying a therapeutic protocol that would be safely translatable to the clinical setting.