Induction of Transforming Growth Factor Beta Receptors following Focal Ischemia in the Rat Brain

Transforming growth factor-beta s (TGF-beta s) regulate cellular proliferation, differentiation, and survival. TGF-beta s bind to type I (TGF-beta RI) and II receptors (TGF-beta RII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-beta RIII). TGF-beta may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-beta is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-beta 1-3 after MCAO. To establish how TGF-beta s exert their actions following MCAO, the present study describes the induction of TGF-beta RI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-beta RI had significant expression: neurons in cortical layer IV contained TGF-beta RI. At 24 h after the occlusion, no TGF-beta receptors showed induction. At 72 h following MCAO, all four types of TGF-beta receptors were induced in the infarct area, while TGF-beta RI and RII also appeared in the penumbra. Most cells with elevated TGF-beta RI mRNA levels were microglia. TGF-beta RII co-localized with both microglial and endothelial markers while TGF-beta RIII and Alk1 were present predominantly in endothels. All four TGF-beta receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-beta RIII was further induced as compared to 72 h after MCAO. At this time point, TGF-beta RIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-beta receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-beta receptor expression is preceded by increased TGF-beta expression. TGF-beta RI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-beta RII, and RIII in endothels within the infarct where TGF-beta 1 may be their ligand. At later time points, TGF-beta RIII may also appear in glial cells to potentially affect signal transduction via TGF-beta RI and RII.