Ischemic stroke (IS), the leading cause of death and long-term disability in humans, imposes a substantial burden on the global economy (Feigin et al., 2018). During the pathological process of IS, the obstruction of blood vessels hampers oxygen supply to the brain, leading to severe brain dysfunction. Presently, the primary therapeutic approaches for IS primarily revolve around recombinant tissue plasminogen activators and interventional therapy. However, their clinical utility is restricted by the narrow therapeutic time window (Behera et al., 2020). Hence, there is a clear imperative to explore safe and effective novel remedies for IS.
Therapeutic angiogenesis has emerged as a prominent global research focus in IS (Wittko-Schneider et al., 2014). Research indicates that the density of neovascularization in the ischemic penumbra correlates positively with the survival of IS patients, with cerebral angiogenesis potentially offering crucial neurovascular substrates for neuronal remodeling (Krupinski et al., 1994; Zong et al., 2020). Nevertheless, IS patients encounter limited compensatory neovascularization, alongside issues of vascular nonreflow and exacerbated blood-brain barrier (BBB) leakage (Li et al., 2007). Therefore, the administration of therapeutic agents becomes imperative for promoting IS angiogenesis. However, preclinical treatments involving cerebral targeted injections of vascular endothelial growth factor A (VEGFA) have proven ineffective, attributed to exacerbated brain tissue damage resulting from elevated vascular permeability and decreased perfusion (Zhang et al., 2000). This underscores that safeguarding vascular structures and function may hold greater promise for IS treatment than simply promoting angiogenesis.
According to traditional Chinese medicine (TCM) theory, IS falls under the category of blood stasis syndrome (Chen et al., 2020). Numerous studies have highlighted the effectiveness of the "stasis-removing and regeneration-promoting" treatment principle for IS (Li et al., 2017; Liu et al., 2016). This academic ideology closely aligns with the concept of angiogenesis in Western medical theories. Taohong Siwu decoction (THSWD), originating from the Golden Mirror of Medicine in the Qing Dynasty, is a classic remedy for "stasis-removing and regeneration-promoting." Its components include Prunus persica (L.) Batsch, Carthamus tinctorius L, Angelica sinensis (Oliv.) Diels, Rehmannia glutinosa (Gaertn.) DC, Ligusticum chuanxiong Hort, and Paeonia lactiflora Pall (Xia et al., 2021). THSWD, with its complex composition, has shown promise in alleviating cerebral ischemia-reperfusion injury (CIRI) by modulating multiple pathways, including angiogenesis promotion (Chen et al., 2020; Li et al., 2015; Shi et al., 2023; Wang et al., 2020). However, the protective effects of THSWD on neovascular structures and function, as well as its molecular mechanisms, remain undisclosed.
Integrative pharmacology, commencing with overall pharmacodynamics, facilitates the exploration of molecular mechanisms and downstream metabolic pathways of active components of TCM during disease intervention. It offers a new research direction for the intricate TCM system in IS treatment (Haiyu et al., 2016). In this study, we constructed a middle cerebral artery occlusion/reperfusion (MCAO/R) model and comprehensively investigated the protective effects of THSWD on neovascular structures and function, alongside the underlying molecular mechanisms.
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