Abstract
Prostaglandin E2 (PGE2) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application of PGE2 induces an EP1-mediated constriction strongly argues against its direct action on arterioles during neurovascular coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted the role of capillaries in sensing neuronal activity and propagating vasodilatory signals to the upstream penetrating parenchymal arteriole. Here, we examined the effect of capillary stimulation with PGE2 on upstream arteriolar diameter using an ex vivo capillary-parenchymal arteriole preparation and in vivo cerebral blood flow measurements with two-photon laser-scanning microscopy. We found that PGE2 caused upstream arteriolar dilation when applied onto capillaries with an EC50 of 70 nM. The response was inhibited by EP1 receptor antagonist and was greatly reduced, but not abolished, by blocking the strong inward-rectifier K+ channel. We further observed a blunted dilatory response to capillary stimulation with PGE2 in a genetic mouse model of cerebral small vessel disease with impaired functional hyperemia. This evidence casts previous findings in a different light, indicating that capillaries are the locus of PGE2 action to induce upstream arteriolar dilation in the control of brain blood flow, thereby providing a paradigm-shifting view that nonetheless remains coherent with the broad contours of a substantial body of existing literature.
Highlights
As a leading cause of stroke and dementia, cerebral small vessel diseases (SVDs) pose a horrendous threat to the elderly population (Pantoni, 2010; Wardlaw et al, 2019)
We have recently demonstrated that activation of the epidermal growth factor receptor (EGFR) by its ligand heparin-binding EGF-like growth factor (HB-EGF) ameliorates the cerebral vascular deficits of the SVD mouse—including impaired functional hyperemia (Capone et al, 2016; Dabertrand et al, 2021)
We previously reported that activation of the epidermal growth factor receptor (EGFR) by its ligand heparin-binding EGF-like growth factor (HB-EGF) ameliorates the cerebral vascular deficits of the SVD mouse—including neurovascular coupling and functional hyperemia deficits (Capone et al, 2016; Dabertrand et al, 2021)
Summary
As a leading cause of stroke and dementia, cerebral small vessel diseases (SVDs) pose a horrendous threat to the elderly population (Pantoni, 2010; Wardlaw et al, 2019). We have recently demonstrated that activation of the epidermal growth factor receptor (EGFR) by its ligand heparin-binding EGF-like growth factor (HB-EGF) ameliorates the cerebral vascular deficits of the SVD mouse—including impaired functional hyperemia (Capone et al, 2016; Dabertrand et al, 2021) Part of this effect is mediated by reenabling capillaryto-arteriole signaling during the neurovascular coupling that underpins functional hyperemia (Dabertrand et al, 2021). Action potentials increase extracellular K+ concentration which activates the strong inward-rectifier K+ (Kir2.1) channel in capillary endothelial cells (cECs) This creates a hyperpolarizing signal that rapidly propagates to upstream arterioles, driving vasodilation and local hyperemia (Longden et al, 2017; Harraz et al, 2018a; Moshkforoush et al, 2020). We showed that both HB-EGF and systemic injection of exogenous PIP2 improved functional hyperemia deficits in SVD mice by restoring capillary-to-arteriole signaling
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