Abstract
Restoration of cerebral blood flow (CBF) and upregulation of angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Here, we investigated for the first time the role of PTX3 in long-term CBF, angiogenesis, and neuronal viability after ischaemic stroke induced by transient middle cerebral artery occlusion (MCAo). Lack of PTX3 had no effect on early brain damage, but significantly impaired restoration of CBF, 14 and 28 days after MCAo, compared to wild-type (WT) mice. Immunohistochemical analysis revealed that PTX3 KO mice have significantly greater neuronal loss, significantly decreased vessel diameter, vessel proliferation, vascular density, and reactive astrocytes and decreased expression of vascular endothelial growth factor receptor 2 (VEGR2), vascular extracellular matrix (ECM)-proteins (collagen IV, laminin), and integrin-β, in the ipsilateral (stroke) hemisphere compared to WT mice, 28 days after MCAo. Therefore, PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia. Collectively, these findings demonstrate the potential and clinical relevance of PTX3 as a promising therapeutic target, providing sustained long-term post-stroke neurovascular repair and reducing the loss of neurons.Key messagesPentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke.Restoration of cerebral blood flow (CBF) and angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia.PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia.
Highlights
A rapid and sustained re-establishment of normal cerebral blood flow (CBF) after ischaemic stroke is associated with a better outcome and improved functional recovery
Assessment of infarct volume using cresyl violet staining revealed no significant difference in lesion volumes in Pentraxin 3 (PTX3) KO mice compared to WT mice 28 days after middle cerebral artery occlusion (MCAo) (Fig. 1a)
The role of the acute phase protein PTX3 on CBF after cerebral ischaemia has not been previously studied, and here, we are the first to show that PTX3 is a key mediator of long-term CBF recovery
Summary
A rapid and sustained re-establishment of normal cerebral blood flow (CBF) after ischaemic stroke (known as reperfusion) is associated with a better outcome and improved functional recovery. Experimental studies have reported that angiogenesis leads to the formation of new blood vessels after ischaemia and promotes recovery [3]. We have previously shown that brain PTX3 expression is upregulated after experimental stroke in the ipsilateral (stroke) hemisphere in mice, promoting recovery in the brain by reducing oedema and improving blood-brain barrier (BBB) integrity by enhancing glial scar formation [6]. Published data from our group suggests that PTX3 promotes angiogenesis 14 days after experimental stroke, demonstrated by a decrease in vasculature, fewer
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