Title : Effects of 20-HETE on angiogenesis and neuroplasticity after experimental ischemic stroke
20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 (CYP450) metabolite of arachidonic acid (AA), is one of the primary eicosanoids in most of microcirculatory beds. Studies have indicated that this compound has important physiological and pathological functions in the modulation of vascular tone, ion transport, cellular proliferation, and inflammation reaction. Both we and others have demonstrated that 20-HETE plays an important role in acute phase of ischemic stroke. However, little is known about the effect of 20-HETE on stroke recovery. We found that 20-HETE promotes angiogenesis both in cell culture experiments and animal model of experimental stroke. Besides, we further investigated the crosstalk between the brain and systemic responses in blood to explore the underlying mechanisms of the effect of 20-HETE on angiogenesis. We demonstrated that the expression of CYP 4A is upregulated in reactive astrocytes which can release 20-HETE that promotes endothelial progenitor cell (EPC)-mediated neurovascular remodeling during stroke recovery. siRNA suppression of CYP 4A in astrocytes or 20-HETE inhibitor prevents this effect. In a mouse model of transient focal cerebral ischemia, reactive astrocytes in the peri-infarct cortex upregulate CYP 4A at 14d poststroke, along with an accumulation of endogenous EPCs. In vivo siRNA suppression of CYP 4A blocks this EPC response, reduces peri-infact angiogenesis, and worsens neurological deficits. Taken together, we first demonstrated a positive influence of 20-HETE in angiogenesis in later stages of poststroke mice. Furthermore, these molecular and in vivo findings also support a previously undescribed mechanism of crosstalk between reactive astrocytes and EPCs wherein 20-HETE promotes neurovascular remodeling and functional recovery after ischemic stroke.