Vascular Endothelial Growth Factor Augments the Tolerance Towards Cerebral Stroke by Enhancing Neurovascular Repair Mechanism

Abstract

The breakdown of the blood–brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood–brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential.

Intermittent hypoxia protects against hypoxic-ischemic brain damage by inducing functional angiogenesis

“…The sudden cessation of blood supply to parts of the brain is an important cause of IS, which can lead to neurovascular uncoupling and secondary neurological impairment. 3 Functional cerebrovascular microcirculation provides oxygen and nutrients to the central nervous system and improves the ischemic-hypoxic tolerance of brain tissue. This can restore perfusion to the infarcted area in time and prevent the occurrence of IS or improve the prognosis of IS in a more durable manner.…”

“…The irreversible damage in the microvasculature of the brain is a key cause of secondary brain injury in IS. 3 This can lead to impaired neurological function and decreased motor or cognitive function, which can severely impact the quality of life. 4 Although IS brain recovery is closely related to vascular protection, no successful therapies are available.…”

Advancing stroke therapy: A deep dive into early phase of ischemic stroke and recanalization

“…Moreover, early poststroke activation of VEGF receptor 2 has been found to hinder the receptor 1-dependent neuroprotection afforded by the endogenous ligand, which highlights the importance of not only the timing but also the specific receptor-mediated actions of VEGF in determining its effects on stroke outcomes. 94,95 The timing and amount of VEGF delivery is critical, as excess levels in the acute stage can worsen injury, while controlled expression during recovery promotes regeneration. Short-term anti-VEGF therapy in the initial injury phase, followed by pro-angiogenic VEGF treatment in the late phase, could represent an optimal therapeutic approach.…”

VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases

“…Although, for some publications the distinction between VEGFA or an isoform of VEGFA is not highlighted. Fortunately, VEGFA treatment has been shown to be beneficial to stroke recovery in animal models [ 29 , 30 , 31 , 32 ]. The administration of VEGFA resulted in the reduction of lesion size in a mouse model of TBI [ 26 ].…”