Gliovascular interface abnormality in mice with endothelial cell senescence. Issue 2 (26th October 2022)

• Record Type: Journal Article
• Authors: Kawauchi, Shoji; Mizoguchi, Taiji; Horibe, Sayo; Tanaka, Toru; Sasaki, Naoto; Ikeda, Koji; Emoto, Noriaki; Hirata, Ken‐ichi; Rikitake, Yoshiyuki
• Is Part Of: Glia. Volume 71:Issue 2(2023)
• Page Start: 467
• Page End: 479
• Publication Date: 2022-10-26
• Subjects: aquaporin‐4 -- astrocyte -- endothelial cell senescence -- laminin -- pericyte; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.24287
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: In the brain, neurons, glial cells, vascular endothelial cells (ECs), and mural cells form a functional structure referred to as the neurovascular unit (NVU). The functions of the NVU become impaired with aging. To gain insight into the mechanism underlying the aging‐related changes in the NVU, we characterized in the present study the gliovascular interface in transgenic mice expressing a dominant‐negative form of the telomeric repeat‐binding factor 2 (TERF2) specifically in ECs using the Tie2 promoter. In these transgenic mice, senescence occurred in the cerebral ECs and was accompanied by upregulation of the mRNAs of proinflammatory cell adhesion molecules and cytokines. It is noteworthy that in the deep layers of the cerebral cortex, astrocytes exhibited an increase in the signals for S100β as well as a decrease in the polarization of the water channel aquaporin‐4 (AQP4) to the perivascular endfeet of the astrocytes. Mechanistically, the perivascular localization of dystroglycan and its ligand, laminin α2, was decreased, and their localization correlated well with the perivascular localization of AQP4, which supports the notion that their interaction regulates the perivascular localization of AQP4. The diminished perivascular localization of laminin α2 may be attributed to its proteolytic degradation by the matrix metalloproteinase‐2 released by senescent ECs. Pericyte coverage was increased and negatively correlated with the decrease in the perivascular localization of AQP4. We propose that aging‐related changes in ECs induce a mild morphological alteration of astrocytes and affect the localization of AQP4 at the gliovascular interface. Main Point: In transgenic mice with premature senescence of endothelial cells, a decrease in astrocytes is seen in the perivascular localization of aquaporin‐4, dystroglycan, and laminin α2 in the deep layers of the cerebral cortex.