Table 2.
Location and function of ECM ligands and their receptors at the BBB and changes in physiology and CNS disease.
| ECM ligand | ECM receptor/anchor | ECM ligand location and function in BBB |
ECM ligand changes in CNS diseases |
|---|---|---|---|
| Laminin isoforms: Laminin 8 (α4β1γ1; 411) Laminin 10 (α5β1γ1; 511) Laminin1 (α1β1γ1; 111) Laminin 2 (α2β1γ1; 211) |
α-dystroglycan Integrins: α6β1, α3β1, α6β4, αvβ3/β1, α5β1, αvβ5, α1β1, α2β1, α7β1 |
Present in endothelial and parenchymal BM [1, 2] BM assembly [3] Ligand for astrocyte endfeet anchoring through dystroglycan Increasing TEER of BCEC [4] Barrier for leukcocyte translocation (laminin α5) [1] |
Stroke model MCAO: BM laminin reduction over time [5] MS: leukocyte degradation of laminin [6] |
| Collagen type IV | Integrins: α1β1, α2β1, α3β1 |
Present in BM of postcapillary venules and capillaries [5] BM stabilization [7] Increasing TEER of BCEC [4] |
Stroke models MCAO, subarachnoid hemorrhage: Reduction collagen IV [5, 8] Mutations in col4a1 linked with hemorrhagic stroke [9] |
| Fibronectin | Integrins: α5β1, α4β1, αvβ3 |
Increasing TEER of BCEC [4] EC proliferation and morphology [10] |
Stroke model MCAO: loss of cellular fibronectin [5] |
| Nidogen (enactin) | Integrins: αvβ3, α3β1 | Stabilization of brain capillary BM; reduced BM in nidogen1 KO [11] |
|
| Agrin (B/z0 isoforms) | α-dystroglycan | EC and parenchymal BM [12] barrier formation [13] |
Stroke model ischemia and reperfusion: loss agrin mRNA and protein [14] Absence in leaky tumor vessels [15] AD: fragmentation at BM and plaque formation [16] |
| Perlecan | α-dystroglycan Integrins: β1 and β3, α2β1 |
EC and parenchymal BM [12] Vessel stabilization [17] |
Stroke model in baboons: loss perlecan [18] |
| SPARC | Expressed in CNS blood vessels and astrocytes in spatiotemporal manner [19] Inhibited collagen IV increased TEER of BCEC in vitro [4] Inhibits VEGF-stimulated EC proliferation [20] |
Stroke model ischemia and reperfusion: loss SPARC [14] |
|
| Fibrinogen | Integrins: αvβ3, αMβ2 (MAC-1) VE-cadherin |
Not present in healthy adult brain | After increased BBB permeability: deposition of fibrinogen and conversion to fibrin in brain [21–23] Functions in animal models of MS [24], AD [25], brain injury [26], and ischemia/hypoxia [27] |
| Osteopontin | Integrins: αvβ1, αvβ3, αvβ5, α4β1, α5β1, α8β1, α9β1 |
Not present in healthy adult brain | Stroke models hypoxia- ischemia and MCAO: upregulation and secretion of osteopontin by microglia, macrophages, neurons and astrocytes [28–30] Protective [30, 31] |
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