Inducible nitric oxide production and expression of transforming growth factor-β1 in serum and CSF after cerebral ischaemic stroke in man

A residual blood supply to the ischaemic brain is a crucial determinant for tissue survival. Early changes in the vascular network and subsequent angiogenesis may be mediated by short-lived molecules like nitric oxide (NO) or growth factors such as transforming growth factor-β1 (TGF-β1). Although TGF-β1 can inhibit NO production, this interaction has not been studied after ischaemia in humans. Serum samples were taken from patients at 24 h and 6 months and cerebrospinal fluid (CSF) samples at 24 h and 1 week later for possible correlation between the two factors. Tissue expression of TGF-β1 and of the inducible isoform of NO synthase (NOS2) was assessed by immunohistochemistry. CSF levels of NO^-₂/NO^-₃ as well as total (active + latent) TGF-β1 were higher in stroke patients as compared to controls 24 h after the stroke. Both NO^-₂/NO^-₃ and TGF-β1 were lower 6 months after the stroke compared to 24 h. Levels of NO^-₂/NO^-₃ correlated with levels of TGF-β1 within the time points (P = 0.041, Kendall correlation coefficient). There was a strong staining for NOS2 in brain tissue sections in neurones, reactive astrocytes, infiltrating white blood cells, and endothelial cells of larger microvessels. TGFβ1 expression was mainly limited to neurones and reactive astrocytes. These findings suggest that the interaction between TGF-β1 and NOS2 might be important for angiogenesis after cerebral ischaemia and may indicate that TGF-β1 is upregulated as a negative feedback response to elevated levels of NO.