Abstract
Russian Barriergenesis is the process of maturation of the primary vascular network of the brain responsible for the establishment of the blood-brain barrier. It represents a combination of factors that, on the one hand, contribute to the process of migration and tubulogenesis of endothelial cells (angiogenesis), on the other hand, contribute to the formation of new connections between endothelial cells and other elements of the neurovascular unit. Astrocytes play a key role in barriergenesis, however, mechanisms of their action are still poorly examined. We have studied the effects of HIF-1 modulators acting on the cells of non-endothelial origin (neurons and astrocytes) on the development of the blood-brain barrier in vitro. Application of FM19G11 regulating expression of HIF-1 activity and GSI-1 suppressing gamma-secretase and/or proteasomal activity resulted in the elevated expression of thrombospondins and matrix metalloproteinases in the developing blood-brain barrier. However, it caused the opposite effect on VEGF expression thus promoting barrier maturation in vitro. Bar'erogenez – éto protsess sozrevaniia pervichnoĭ sosudistoĭ seti golovnogo mozga, pri kotorom proiskhodit stanovlenie gematoéntsefalicheskogo bar'era. On predstavliaet soboĭ sochetanie faktorov, kotorye, s odnoĭ storony, sposobstvuiut protsessu migratsii i tubulogenezu éndotelial'nykh kletok (angiogenez), s drugoĭ storony, sposobstvuiut formirovaniiu novykh sviazeĭ mezhdu éndoteliotsitami i drugimi élementami neĭrovaskuliarnoĭ edinitsy. Perivaskuliarnye astrotsity vnosiat znachitel'nyĭ vklad v bar'erogenez, odnako mekhanizmy étogo uchastiia malo izucheny. V rabote issledovano deĭstvie moduliatorov HIF-1 v kletkakh neéndotelial'noĭ prirody (neĭrony i astrogliia) na formirovanie gematoéntsefalicheskogo bar'era in vitro. Primenenie FM19G11, reguliruiushchego ékspressiiu HIF-1, i GSI-I, podavliaiushchego aktivnost' gamma-sekretazy i/ili proteasom, privodit k uvelicheniiu ékspressii trombospondinov i matriksnykh metalloproteinaz v razvivaiushchemsia gematoéntsefalicheskom bar'ere, no okazyvaet raznonapravlennyĭ éffekt v otnoshenii produktsii VEGF, chto, v tselom, sposobstvuet sozrevaniiu bar'era in vitro.