Trombin és ischémia együttes hatása a vér-agy-gát sejtjeire = The effects of thrombin and ischemia on the cells of the blood-brain-barrier

A ver-agy-gat (VAG) sejtjeiben, agyi kapillaris endotel sejtekben es asztrocitakban vizsgaltuk trombin es receptorainak kolcsonhatasat.. A trombin szignalizacio meghatarozott lepeseit tanulmanyoztuk, az intracellularis Ca szint valtozasat es az ERK foszforilaciot. Kimutattuk a PAR-1 es PAR-4 thrombin receptorok expressziojat es a ket receptor elterő Ca- ill. ERK szignalizaciojat. Angiogenezis temaban a tumor indukalt angiogenezis kvantitativ modeljet dolgoztuk ki. A tumor MVD (mikrovaszkularis denzitas) csokkenese ill. novekedese altalaban diagnosztikus parameterkent hasznalt a tumor terapia soran. Az altalunk kidolgozott kvantitativ angiogenezis model predikcioi szerint viszont tumor mikroerek szama, ezek denzitasa (MVD, mikrovaszkularis denzitas) nem feltetlenul all osszhangban a tumor novekedesevel. Ez a predikcio osszhangban van a melanomaban publikalt kiserleti angiogenezis tapasztalataival. Altalanositva, a tumor indukalt angiogenezis kezdeti lepeseiben a tumor MVD-n kivul fontos szerepe van az eredeti szoveti kornyezet mikrovaszkulasris surusegenek, illetve a tumor metabolikus aktivitasanak. | Protease activated receptors (PARs) mediate thrombin signaling of brain endothelial cells and thrombin accelerate intracerebral ischemia. We measuered PAR expression, [Ca2+]i and extracellular-signal-regulated kinase (ERK) phosphorylation in brain capillary endothelial cells. Calcium imaging confirmed that the cells responded to PAR-1 and PAR-4 agonist peptide by an elevation of [Ca2+]i , the shape of [Ca2+]i transient was different. Ca2+ entry was required to maintain oscillations. A method to culture brain capillary endothelial cells on glass, covered by Matrigel was worked out.The procedure yields cells that express tight junction proteins ZO-1, claudin-5 and ?-catenin. Glass coverslips covered with Matrigel provide a stable and low background base for microfluorimetric calcium measurements. The transformation of the regular vasculature in normal tissue into a inhomogeneous tumor speci?c capillary network is described. The theoretical model incorporates tumor growth, vessel cooption, neo-vascularization, vessel collapse and cell death.Compartmentalization of the tumor into regions differing in vessel density, diameter and in necrosis is observed in agreement with the vessel morphology found in human melanoma. The model predicts that microvascular density (MVD), regarded as an important diagnostic tool in cancer treatment, does not determine the tempo of tumor progression. Instead it is suggested that the MVD of the original tissue and the metabolic demand of the tumor cell plays the role in tumor growth.