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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3270-3278.
Prepublished online as a Blood First Edition Paper on December 14, 2006; DOI 10.1182/blood-2006-08-043125.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Tissue-type plasminogen activator–mediated shedding of astrocytic low-density lipoprotein receptor–related protein increases the permeability of the neurovascular unit
Rohini Polavarapu1,
Maria Carolina Gongora1,
Hong Yi2,
Sripriya Ranganthan3,
Daniel A. Lawrence4,
Dudley Strickland5, and
Manuel Yepes1
1 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA;
2 Microscope Core Center, Emory University, Atlanta, Georgia;
3 Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore;
4 Department of Internal Medicine, University of Michigan, Ann Arbor;
5 Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore
The low-density lipoprotein receptor–related protein (LRP) is a member of the LDL receptor gene family that binds several ligands, including tissue-type plasminogen activator (tPA). tPA is found in blood, where its primary function is as a thrombolytic enzyme, and in the central nervous system where it mediates events associated with cell death. Cerebral ischemia induces changes in the neurovascular unit (NVU) that result in brain edema. We investigated whether the interaction between tPA and LRP plays a role in the regulation of the permeability of the NVU during cerebral ischemia. We found that the ischemic insult induces shedding of LRP's ectodomain from perivascular astrocytes into the basement membrane. This event associates with the detachment of astrocytic end-feet processes and the formation of areas of perivascular edema. The shedding of LRP's ectodomain is significantly decreased in tPA deficient (tPA–/–) mice, is increased by incubation with tPA, and is inhibited by the receptor-associated protein (RAP). Furthermore, treatment with either RAP or anti-LRP IgG results in a faster recovery of motor activity and protection of the integrity of the NVU following middle cerebral artery occlusion (MCAO). Together, these results implicate tPA/LRP interactions as key regulators of the integrity of the NVU.
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