As the common type of stroke, ischemic stroke is the leading cause of the permanent disability worldwide, and brings about great burden for the global medical care (Low et al., 2014a). To date, the early recovery of cerebral blood flow (CBF) has been a promising strategy to treat stroke, while a great number of patients have a poor prognosis due to the occurrence of “no-reflow” phenomenon, which was referred as the impaired recanalization after reperfusion (Cai et al., 2017; Cenko et al., 2016; Guo et al., 2022). Thus, the treatments targeting no-reflow phenomenon could lead to the improved outcome for stroke patients.

Pericytes (PCs) surrounded by the basal lamina play a key role in regulating capillary blood flow by contracting and dilating (Yemisci et al., 2009). The inhibition targeting PC contraction significantly improves the CBF restoration after ischemia, and alleviates the cerebral hypoxia and infarction in stroke (Korte et al., 2022). The recent study further suggests the involvement of PC contraction in the no-reflow phenomenon after reperfusion (Guo et al., 2022). Collectively, these studies suggest that the interventions against PC contraction could be clinical benefit for the patients with ischemic stroke.

As a member of phosphoinositide-3-kinase (PI3K) family, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit Delta (PIK3CD/PI3Kδ) is involved in the leukocyte regulation (Uehara et al., 2017). Particularly, Low et al. found that PI3Kδ inhibition attenuated the neuro-inflammation in a stroke model via regulating microglia activity (Low et al., 2014a). However, the role of PI3Kδ in the PC contraction during ischemic stroke has not been explored yet. The upregulated PI3Kδ accounts for the increased vascular contractility in type I diabetes (Pinho et al., 2010), while the inactivation of PI3Kδ alters the PC coverage during tumor angiogenesis (Soler et al., 2013). The Single Cell RNA-seq Gene Expression database further suggests an abundant PI3Kδ expression in PCs among the cerebrovascular cells (betsholtzlab.org). In this context, we propose that PI3Kδ may be a critical regulator of PC function during ischemic stroke.

As an important pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) disrupts the PC-mediated cerebral microcirculation in traumatic brain injury (Zheng et al., 2023), and PI3Kδ has shown the property to reduce TNF level during ischemic stroke (Low et al., 2014a). Besides, TNF-α induces an evident upregulation of transient receptor potential vanilloid type 2 (TRPV2) in human dental pulp cells, which is a calcium-permeable cation channel protein (Aguettaz et al., 2017; Liu et al., 2019; Chaudhuri et al., 2021). TRPV2 inhibition promotes the secretion of nerve growth factor (NGF) in astrocytes after the oxygen-glucose deprivation and reoxygenation (OGD/R) induction (Zhang et al., 2016), suggesting the neuroprotective role of TRPV2 suppression. The blockade of calcium influx contributes to the alleviation of PC contraction during ischemic stroke (Guo et al., 2022). TRPV2 downregulation alleviates the Ca2+ overload in cardiomyocytes, thus improving the myocardial ischemia reperfusion injury in mice (Li et al., 2019). Consequently, it is supposed that PI3Kδ may facilitate PC contraction via TNF-α-induced TRPV2 upregulation.

In summary, this study is designed to investigate whether PI3Kδ plays a novel role in PC contraction, and the inactivation of PI3Kδ has the beneficial effects on ischemic stroke.