Intracerebral hemorrhage (ICH) is a devastating stroke subtype that accounts for 10–20% of strokes worldwide (Aronowski and Zhao, 2011) and carries a one-month mortality rate of 40% (Hemphill 3rd et al., 2015); those who survive are frequently left permanently disabled (Al-Shahi Salman et al., 2009). Hypertension is the leading risk factor for ICH (Hemphill 3rd et al., 2015), followed by cerebral amyloid angiopathy and anticoagulant use (Al-Shahi Salman et al., 2009). The primary insult is mechanical disruption from the hematoma, after which secondary damage driven by inflammation and oxidative stress amplifies neuronal injury (Aronowski and Zhao, 2011; Hemphill 3rd et al., 2015). Current therapeutic options are limited; blood-pressure reduction provides modest benefit (Al-Shahi Salman et al., 2009), whereas surgical evacuation yields inconsistent results (Aronowski and Zhao, 2011), underscoring the urgent need for novel interventions.

Angiogenesis plays a key role in brain repair after hemorrhage, as new vessel formation restores blood flow and supports tissue remodeling (Ergul et al., 2012). In animal models of ICH, increased capillary density correlates with better neurological recovery (Hatakeyama et al., 2020). Human imaging studies confirm vascular changes post-stroke (Ergul et al., 2012), and delayed angiogenesis leads to poor prognosis (Hatakeyama et al., 2020). Factors influencing this process include hypoxia and growth signals (Ergul et al., 2012), and therapeutic strategies aim to enhance vessel growth (Hatakeyama et al., 2020). Challenges involve the timing and stability of new vessels, as excessive permeability can worsen edema (Ergul et al., 2012).

Vascular endothelial growth factor (VEGF) stands as a central mediator of angiogenesis (Greenberg and Jin, 2013). This protein binds to receptors on endothelial cells, promoting proliferation and migration (Lange et al., 2016). In stroke, VEGF levels rise in response to ischemia (Greenberg and Jin, 2013), and signaling through VEGF receptor-2 (VEGF-R2) drives vessel sprouting (Lange et al., 2016). Studies show improved functional outcomes with exogenous VEGF administration (Greenberg and Jin, 2013), but early delivery risks increased bleeding (Lange et al., 2016). Late-phase VEGF effects support neuroprotection (Greenberg and Jin, 2013), and interactions with other pathways amplify its actions (Lange et al., 2016). VEGF regulation involves transcription factors and downstream effectors (Greenberg and Jin, 2013).

ETS1 (E-twenty-six specific 1) functions as a key transcription factor in vascular biology, where it regulates genes involved in extracellular matrix remodeling (Zhan et al., 2005). During vessel formation, its expression is notably increased (Watanabe et al., 2004). Studies employing knockout models have demonstrated that the absence of ETS1 leads to defective angiogenesis (Wei et al., 2009). Within endothelial cells, ETS1 directly binds to the promoters of angiogenic growth factors (Watanabe et al., 2004). Post-translational modifications, including acetylation, serve to enhance its transcriptional activity (Zhan et al., 2005; Wei et al., 2009; Watanabe et al., 2004). Furthermore, ETS1 establishes important connections to inflammatory signaling pathways (Zhan et al., 2005). In various pathological contexts, the function of ETS1 may become dysregulated (Zhan et al., 2005). Consequently, targeting ETS1 holds potential for modulating processes involved in vascular repair (Zhan et al., 2005; Wei et al., 2009; Watanabe et al., 2004).

Phoenixin (PNX) is a phylogenetically conserved neuropeptide derived from the prohormone small integral membrane protein 20 (SMIM20) and exists in two major active isoforms: PNX-14 (14 amino acids) and PNX-20 (20 amino acids) (Muzammil et al., 2024). Both isoforms are generated via post-translational processing of SMIM20 (Muzammil et al., 2024). PNX is widely expressed in the central nervous system (e.g., hypothalamus, hippocampus, cerebral cortex) and in peripheral tissues, including the heart and vasculature (Schalla and Stengel, 2018). Beyond its well-documented roles in appetite regulation, reproductive hormone secretion, and anxiolytic effects (Muzammil et al., 2024; Schalla and Stengel, 2018; Friedrich and Stengel, 2023), emerging evidence suggests a potential role for PNX in circulatory system physiology and vascular homeostasis, including cardioprotective effects during ischemia/reperfusion injury and modulation of endothelial function under oxidative stress (Muzammil et al., 2024; Schalla and Stengel, 2018; Friedrich and Stengel, 2023). The biological actions of phoenixin are mediated through interactions with G protein-coupled receptors (Muzammil et al., 2024; Schalla and Stengel, 2018; Friedrich and Stengel, 2023). G protein-coupled receptor 173 (GPR173) serves as the putative receptor for PNX (Stein et al., 2016; Yosten et al., 2013). This orphan receptor, belonging to the class A (rhodopsin-like) GPCR superfamily, is expressed in the brain and in cardiovascular-relevant regions, and its distribution overlaps with that of the peptide (Stein et al., 2016; Yosten et al., 2013). The PNX/GPR173 axis may thus play a role in maintaining vascular integrity and function (Stein et al., 2016; Yosten et al., 2013).

Despite advances in understanding post-hemorrhage repair, a significant knowledge gap exists regarding the contribution of neuropeptide systems to vascular recovery (Aronowski and Zhao, 2011). Specifically, the role of the phoenixin axis in post-stroke angiogenesis remains undefined. Earlier research on phoenixin has focused on its reproductive functions (Friedrich and Stengel, 2023). Additional studies have described its involvement in metabolic regulation (Muzammil et al., 2024) and stress responses (Schalla and Stengel, 2018). Furthermore, the molecular basis linking phoenixin to pro-angiogenic VEGF signaling in hemorrhagic stroke models is not well characterized (Greenberg and Jin, 2013). The transcriptional regulation of such pathways by ETS1 also warrants detailed investigation in the setting of brain hemorrhage (Zhan et al., 2005).

We hypothesize that the phoenixin-14/GPR173 axis stimulates angiogenesis following ICH by activating ETS1-dependent VEGF signaling. This investigation offers novelty by linking a neuropeptide system to post-hemorrhage repair, demonstrating that the phoenixin-14/GPR173 axis is downregulated in disease models and that phoenixin-14 treatment restores its function through specific molecular mechanisms. Combined in vivo and cellular data provide comprehensive evidence to support this hypothesis, and the findings could guide the development of targeted interventions, as improved neurological outcomes may result from modulating this pathway.