The brain function depends on a continuous supply of blood. The blood-brain barrier (BBB), which is formed by vascular cells and glia, separates components of the circulating blood from neurons and maintains the precisely regulated brain milieu required for proper neuronal function. A compromised BBB alters the transport of molecules between the blood and brain and has been associated with or shown to precede neurodegenerative disease. Blood components immediately leak into the brain after mechanical damage or as a consequence of a compromised BBB in brain disease changing the extracellular environment at sites of vascular damage. It is intriguing how blood-derived components alter the cellular and molecular constituents of the neurovascular interface after BBB opening. We recently identified an unexpected role for the blood protein fibrinogen, which is deposited in the nervous system promptly after vascular damage, as an initial scar inducer by promoting the availability of active TGF-β. Fibrinogen-bound latent TGF-β interacts with astrocytes, leading to active TGF-β formation and activation of the TGF-β/Smad signaling pathway. Here, we discuss the pleiotropic effects of potentially vascular-derived TGF-β on cells at the neurovascular interface and we speculate how these biological effects might contribute to degeneration and regeneration processes. Summarizing the effects of the components derived from the brain vascular system on nervous system regeneration might support the development of new therapeutic approaches.