Ang II-mediated effects on BBB integrity in psychiatric and neurological disorders

Abstract

Alterations of the blood-brain barrier (BBB) integrity and permeability is a critical factor implicated in several brain pathologies, including stress-related and neurodegenerative disorders. Growing evidence suggests that the renin-angiotensin system (RAS), a key regulator of vascular homeostasis, also plays a significant role in the pathogenesis and progression of these neurological conditions. Notably, angiotensin II (Ang II) and its downstream signaling pathways contribute to the modulation of BBB properties, directly impacting brain health. While the pharmacological targeting of the RAS has been extensively explored and shown to alleviate neurological and psychiatric symptoms, the molecular mechanisms underlying the complex crosstalk between Ang II and the BBB in these disorders remain insufficiently understood. In this review, we highlight the current literature supporting the contribution of Ang II and its type 1 and type 2 receptor-mediated signaling pathways to the structural and functional integrities of the BBB. We systematically gathered and analyzed relevant studies describing how Ang II disrupts BBB function across various pathological contexts, with an emphasis on stress-related disorders, neurodegenerative diseases and traumatic brain injury (TBI). This consolidated understanding helps refine future research questions and guide hypothesis-driven studies to better dissect the mechanisms underlying the relationship between Ang II signaling and BBB vulnerability.

1. Introduction

The renin-angiotensin system (RAS) has long been recognized as a key regulator of fundamental physiological functions, including fluid and electrolyte balance, blood pressure control, vascular tone, and overall cardiovascular allostasis (Triebel and Castrop, 2024). Beyond these classical roles, accumulating evidence indicates that RAS is also critically involved in maintaining brain homeostasis, where it contributes to the regulation of neural plasticity, neurogenesis and neuroinflammation (Rodríguez-Pallares et al., 2025; Xu et al., 2025). The main effector of RAS signaling is angiotensin II (Ang II), a peptide hormone generated through the proteolytic cleavage of angiotensinogen, which is synthesized not only in the liver but also locally in the brain, primarily by astrocytes and neurons (Rodrigues et al., 2024). This process is initiated by renin—the rate-limiting enzyme of the cascade—-produced by renal juxtaglomerular cells as well as by specific neuronal populations in the amygdala and hypothalamus. Renin catalyses the conversion of angiotensinogen into angiotensin I (Ang I) (Rodrigues et al., 2024; Urmila et al., 2021). Ang I is subsequently converted into Ang II by angiotensin-converting enzyme 1 (ACE1), which is expressed in cerebral vascular endothelium, astrocytes, neurons, as well as in the choroid plexus (Cueto-Ureña et al., 2025). In the central nervous system (CNS), Ang II–dependent signaling orchestrates vasoconstrictive and vasodilatory responses while simultaneously influencing brain functions including cognition and coping behaviors (Campagnole-Santos et al., 2025; Rodríguez-Pallares et al., 2025). In this review, we focus on Ang II in various psychiatric disorders, including major depressive disorder (MDD), anxiety, schizophrenia, and post-traumatic stress disorder (PTSD), as well as in neuropathological conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and multiple sclerosis (Jackson et al., 2018; Tran et al., 2022).

Ang II has distinct affinities for several receptors, including angiotensin type 1 (ATR1) and type 2 (ATR2) receptors, as well as Mas receptor (MasR). These receptors are expressed in vascular and neurovascular endothelial cells, pericytes, and CNS cell types (i.e., neurons, astrocytes and microglia) (Jackson et al., 2018; Kanugula et al., 2026; Vargas Vargas et al., 2022). The peripheral and CNS synthesis of Ang II (Huber et al., 2017; Jackson et al., 2018), as well as its vasoconstrictive and vasodilatory functions in the body and brain (Martyniak and Tomasik, 2022; Vargas Vargas et al., 2022) have been extensively explored. Binding of ATR1 and ATR2 G protein-coupled receptors by Ang II induces opposite effects on the neurovasculature. The activation of ATR1—Ang II's primary target—triggers the Gq-phospholipase C-β signaling pathway, leading to the production of inositol 1,4,5-trisphos-phate and diacylglycerol, and resulting in intracellular calcium release and protein kinase C signaling activation (Bhullar and Dhalla, 2022). Downstream MAPK/ERK- and NF-κB-regulated cascades further promote systemic vasoconstriction, pro-inflammatory responses and endothelial dysfunction, as well as neurovascular disruption and remodeling (Bhullar and Dhalla, 2022). ATR1-regulated neurovascular effects are also accompanied by neuronal changes, including inhibition of the GABAergic neurons within the rostral ventrolateral medulla, which leads to increased release of noradrenaline by the nucleus tractus solitarius and suppression of nitric oxide synthase (NOS) signaling (Huber et al., 2017; Tran et al., 2022). In contrast, ATR2 binding by Ang II stimulates phosphatase-dependent mechanisms, from which dephosphorylation opens potassium channels, induces membrane hyperpolarization, and reduces cellular excitability (Steckelings et al., 2022). ATR2 cascade also enhances endothelial NOS activity, thereby promoting nitric oxide (NO) production and vasodilation (Bhullar and Dhalla, 2022). ATR2-modulated dephosphorylation further downregulates pro-apoptotic and pro-inflammatory signals, supporting neuronal survival and homeostasis. Neuronal growth and synaptic plasticity can also be facilitated by ATR2-potentiated expression of nerve growth factor (NGF) (Umschweif et al., 2014). Although ATR2 is a member of the G-protein coupled family, it does not engage classical features of G protein signaling. Instead, ATR2-dependent pathways generally counteract ATR1-dependent detrimental effects and contribute to brain health through anti-inflammatory and anti-oxidative properties. Despite these well-established molecular cascades, the contribution of Ang II signaling to neurovascular pathophysiology and related diseases remains scarcely described in the literature.

Many preclinical and epidemiological studies have demonstrated the critical implication of RAS in neurodegenerative diseases (e.g., AD and PD) and mental disorders (e.g., MDD and PTSD) (Al-Qahtani et al., 2024; Seligowski et al., 2021b). These CNS disorders are strongly associated with systemic inflammation, characterized by increased circulating levels of monocytes and lymphocytes, as well as elevated secretion of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-2 and tumor necrosis factor-α (TNF-α) (Deslauriers et al., 2018; Kanugula et al., 2026; Levesque et al., 2023). In addition to the heightened production of these pro-inflammatory regulators, pathological neuroinflammation is marked by microgliosis and astrogliosis (Deslauriers et al., 2017; Levesque et al., 2023; Seligowski et al., 2021b).

Coordinated peripheral and CNS immune responses in brain disorders suggest that the blood-brain barrier (BBB) may underlie this intertwined relationship (Kanugula et al., 2026; Seligowski et al., 2021b). The BBB is a highly complex vascular interface that regulates molecular and cellular communication by selectively controlling the traffic of molecule and cells between the bloodstream and CNS. Its cytoarchitecture includes endothelial cells, astrocyte feet, and pericytes (Fig. 1). Transcellular transport across the BBB is governed by tight junction proteins (TJPs; i.e., occludin and claudins) and adherent molecules, such as junctional adhesion molecules (JAMs) and zonula occludens-1 (ZO-1) (Wu et al., 2023). The transmigration of immune cells, in contrast, is primarily regulated by vascular endothelial (VE)-cadherin and platelet endothelial cell adhesion (PECAM)-1, located in the basolateral side of TJPs, along with intercellular adhesion molecule (ICAM) and viscoelastic cell adhesion molecule (VECAM) (Kadry et al., 2020; Steiner et al., 2010). Endothelial junctional gaps are also implicated in mechanical endothelial cell signaling and vascular angiogenesis (Benz and Liebner, 2022). Furthermore, the matrix metalloproteinases (MMPs)—that are regulated by tissue inhibitors of metalloproteinases (TIMPs)—further contribute to immune function by maintaining tissue integrity and supporting cell migration, angiogenesis and extracellular matrix remodeling (Ahmadighadykolaei et al., 2023; Rempe et al., 2016) (Fig. 1).

Fig. 1.

Interaction between angiotensin II (Ang II) and blood-brain barrier (BBB) in stress-related pathologies and neurodegenerative disorders. Ang II exerts excitotoxicity effects via its binding to angiotensin type 1 receptor (ATR1) on endothelial cells and astrocyte feet, as well as via indirect toll-like receptor (TLR4) overexpression in microglial cells (1). Excessive production of matrix metalloproteinase-9 (MMP-9) facilitates the damage repair in endothelial cells (2). Activation of microglial TLR4 lead to increased production and release of pro-inflammatory factors (TNFα, iNOS, NO, TLR4, MyD88) and reactive oxygen species (ROS) which reach the neurovasculature (3). Then, endothelial cells produce regulators of immune cell migration and inflammation (ICAM, PECAM, VCAM) (4), leading to ACE1/ACE2 imbalance and loss of tight junction proteins (claudin and occludin) and adherens junctions (JAM and ZO) (5). The production of ROS results in overactivation of astrocytes in repairing BBB cellular damage of BBB via the release of VEGF and MMPs/TIMPs (6). ACE, angiotensin converting enzyme; ICAM, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; JAM, junctional adhesion molecule; NO, nitric oxide; MyD88, myeloid differentiation primary response 88; PECAM, platelet endothelial cell adhesion molecule; TNFα, tumor necrosis factor α; VCAM, vascular cell adhesion molecule; ZO, zonula occludens.

In pathological contexts, chronic and excessive production of Ang II disrupts BBB cytoarchitecture, triggering abnormal neuroinflammatory responses in endothelial cells, astrocyte feet, and pericytes. This leads to the downregulation of key TJPs (i.e., claudin-3, claudin-5, ZO-1, and occludin), particularly in limbic brain regions (Noureddine et al., 2020; Takata et al., 2021). Nevertheless, the mechanisms linking Ang II to BBB breakdown in the pathophysiology of stress-related disorders, neurodegenerative disorders, and other clinical conditions need to be further clarified. Here, we review the current state of knowledge regarding RAS-BBB interactions, with a specific focus on Ang II in neuropathological settings. Given the growing evidence supporting the therapeutic potential of RAS modulators and antihypertensive agents in neurological and mental disorders (Carnovale et al., 2023), this review highlights the knowledge gaps and provides guidance for advancing our understanding of the neurovascular mechanisms operating at the BBB interface.

2. The implication of Ang II in BBB disruption in animal models of stress-related disorders

Numerous preclinical studies have consistently demonstrated an association between Ang II and stress-related disorders (Table 1). In a renin- and angiotensinogen-deficient mouse model, both males and females displayed elevated BBB permeability in the hippocampus, as evidenced by Evans Blue (EB) leakage (Yanai et al., 2000). Additional work has further linked neurovascular dysfunction and stress-associated phenotypes: similar findings were reported in a two-hit rat model of hypertension, with increased EB leakage and decreased levels of TJPs ZO-1 and occludin consistently observed in the cortex, cerebellum, and diencephalon (Kucuk et al., 2002; Kalayci et al., 2005). These alterations were alleviated by ATR1 pharmacological blockade (i.e., losartan) or antihypertensive agents with antioxidant properties (e.g., atorvastatin) (Kaya et al., 2003; M et al. 2002; Kalayci et al., 2005). Interestingly, in a model of NO blockade-induced hypertension, administration of the TLR4 agonist LPS paradoxically reduced BBB permeability, suggesting that TLR4 activation may exert context-dependent effects on neurovascular integrity (Ahishali et al., 2005).

Table 1.

The contribution of renin-angiotensin system and blood-brain barrier in animal models stress-related disorders

Species	Model/Condition	Findings	References
Rodents – Genetic lines
Mice M/F	Renin- and angiotensinogen-deficient mice	↑ EB leakage ↓ Blood pressure	Yanai et al., 2000
Rodents - Peripherally driven pharmacological activation of RAS
Rat	L-NAME-induced hypertension (1 g/L, PO) and/or Ang II-induced acute hypertension (60 μg/kg, IV)	↑ EB leakage (cortex, cerebellum, diencephalon) that was normalized with treatment with AT1R antagonist losartan (3 mg/kg, IV, 5 days)	Kucuk et al., 2002
		↑ EB leakage (cerebellum and diencephalon) and ↓ ZO-1 and occludin expression that were attenuated with LPS (5 mg/kg, IP for 14 days)	Ahishali et al., 2005
		↑ EB leakage (cortex, cerebellum and diencephalon) and ↓ ZO-1 and occludin expression that were attenuated with the antioxidant properties of atorvastatin (4 mg/kg, SC for 20 days)	Kalayci et al., 2005
Rat	Ang II-induced hypertension (20 ng/kg/min, SC for 14 days)	No changes in HRP leakage in in the cortex, corpus callosum or hippocampus	Pelisch et al., 2010
Rat	Diabetic hypertensive model with L-NAME (0.5 mg/mL, PO) and alloxan (50 mg/kg, IP)	Epinephrine-induced acute vascular injury ↑ EB leakage (cortex, cerebellum, diencephalon), which was normalized with losartan (3 mg/kg, IV, 5 days)	Kaya et al., 2003
Mice	Ang II (2 μg/kg, SC for 14 days)	↑ Blood pressure, EB leakage, and leukocytes/platelets adhesion that were not observed with losartan treatment, in AT1R−/−, or in RANTES−/−mice	Vital et al., 2010
Mice	Ang II-induced hypertension (400 ng/kg/min for 14 days)	↑ leukocyte adhesion to endothelium and EB leakage that were attenuated with antioxidant (TEMPOL, 2 mmol PO starting on 4th day of Ang II treatment)	Zhang et al., 2010
Mice	Ang II-induced hypertension (400–2000 mg/kg, SC for14 days)	↑ brain injury-induced EB leakage and leucocyte/platelet adhesion These Ang II-induced exaggeration of injury effects were lacking in AT1−/−	Nagai et al., 2011
Mice	Ang II (3 ng/kg/min, SC for 3 months)	↑ IgG leakage in hippocampus and cerebral nuclei; ↑ microglial density and soma size	Foulquier et al., 2018
Rat	Ang II (200 μL, 10−5 M, IV)	↑ EB leakage in the hippocampal GABAergic neurons	Hamasaki et al., 2020
Mice	Ang II-induced hypertension (60 ng/kg/min, SC for 14 days)	↑ BBB permeability (2-photon microscopy) that was partially abolished by AT1R deletion in PVM, and completely prevented by AT1R deletion in endothelial cells	Santisteban et al., 2020
Mice	Ang II-induced hypertension (1000 ng/kg/min for 28 days)	↓ short-term memory function; ↑ 3-kDa dextran leakage; ↓ claudin-5 and ↑ caveolae-mediated endocytosis These effects were inhibited by nicotinamide riboside administration (300 mg/g, PO)	Li et al., 2020
Mice	AT1R antagonist irbesartan (50 mg/kg/day, IP for 7 days)	↓ LPS (0.83 mg/kg)-induced BBB disruption and restore expression of occludin and ICAM-1 ↑ blood pressure; ↑ FITC10 leakage in the hypothalamus	Yang et al., 2021
Rat	SHR rat	These effects were prevented by AT1R antagonist losartan (20 mg/kg, PO for 4 weeks) and by TLR4 inhibitor TAK-242 (2 mg/kg, IP for 2 weeks)	Mowry et al., 2021
Rat	Ang II (10 μg/kg, IV)	↑ microvascular damage (vasoconstriction and leakage) in the hypoperfusion/reperfusion model These effects were blunted by pretreatment with AT1R antagonist candesartan (15 mg/kg)	Lapi et al., 2021
Mice	Ang II-induced hypertension (2 μg/kg/min, SC for 10 days)	↑ blood pressure; ↑ BBB permeability to albumin-Alexa fluor 594; ↑ caveolin-1 and Glut-1 (cortex and hippocampus); ↓ claudin-5 (cortex and hippocampus) These effects were prevented by treatment with TGF-β inhibitor (SB-431542, 2 mg/kg every 12 h; IP for 3 days)	Atis et al., 2022
In vitro
Endothelial cells	Ang II (100 nmol/L; 0 to 6 h)	↑ 125I-Albumin permeability and ↓ TEER that were normalized by AT1R blocker telmisartan (1 μmol/L), but not AT2R blocker PD123,319 (1 μmol/L) No changes in occludin and claudin-5 expression	Fleegal-DeMotta et al., 2009
	Ang II (0.1 μM, 8 h or 24 h)	↑ Na—F (376 Da) and BSA (66 kDa) flux; ↓ claudin-5, occludin and ZO-1	Lu et al., 2021
	Ang II (0.1 μM, 24 h)	↓ JAM-A, ZO-1, claudin-5, caveolin-1 and Mfsd2a; ↑ Na—F permeability	Xie et al., 2022
Endothelial cells and BBB model	Ang II (0.1 μM) and/or LPS (1 μg/mL) for 24 h	↓ cell viability, ↑ TLR4, MyD88, iNOS, TNF-α, and caveolin-1 ↑ BSA-FITC across the mono-culture barrier	Xia et al., 2022

ACE, angiotensin-converting enzyme; Ang II, angiotensin II; ATR, angiotensin II receptor; BBB, blood-brain barrier; BSA, bovine serum albumin; BSA-FITC; bovine serum albumin conjugated with fluorescein isothiocyanate; CSF1R, colony stimulating factor 1 receptor; EB, Evans blue; GLUT-1; glucose transporter-1; HRP, horseradish peroxidase; ICAM-1, intercellular adhesion molecule-1; ICV, intracerebroventriculary; iNOS, inducible nitric oxide synthase; IP, intraperitoneally; IV, intravenously; JAM-A, junctional adhesion molecule-A; L-NAME, N (omega)-nitro-L-arginine methyl ester; LPS, lipopolysaccharide; MyD88, myeloid differentiation primary response 88; NA-F, sodium fluorescein; PO, per os; PVM, perivascular macrophages; SC, subcutaneously; SHR, spontaneous hypertensive rats; TEER, transendothelial electrical resistance; TGF-β, tumor growth factor-β; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; ZO-1, zonula occludens-1.

A dose-dependent effect of Ang II has also been demonstrated: chronic infusion of high doses of Ang II disrupted BBB integrity across multiple brain regions (Foulquier et al., 2018; Nagai et al., 2011; Vital et al., 2010; Zhang et al., 2010), whereas low doses produced no measurable effect (Pelisch et al., 2010). Chronic Ang II-induced hypertension was further associated with increased expression of endothelial vesicular (caveolin-1) and glucose (GLUT-1) transporters, together with decreased cortical and hippocampal expression of TJP claudin-5 (Atis et al., 2022; Li et al., 2020). EB accumulation in the hippocampus has been shown to occur preferentially in GABAergic neurons (Hamasaki et al., 2020), underscoring the importance of Ang II chronicity in driving vascular alterations in stress-relevant circuits.

In vitro studies provide converging evidence of Ang II's detrimental vascular effects: exposure of brain endothelial cell monolayers to Ang II increased BBB permeability, reduced transendothelial electrical resistance (TEER), and downregulated levels of claudin-5, occludin, ZO-1, JAM-A, and caveolin-1 (Fleegal-DeMotta et al., 2009; Lu et al., 2021; Xie et al., 2022). These effects were consistently reversed by ATR1 antagonists, supporting ATR1's key in BBB disruption. In rodent models of genetic ATR1 deficiencies or Ang II-induced hypertension, ATR1 blockage with losartan similarly mitigated neurovascular dysfunction (Lapi et al., 2021; Nagai et al., 2011; Vital et al., 2010). Importantly, BBB leakage in spontaneously hypertensive rats was reversed by losartan but not by the vasodilator hydralazine, highlighting the specificity of ATR1 signaling (Mowry et al., 2021). Additionally, paraventricular nucleus (PVN)-specific deletion of ATR1 only partially reduced BBB permeability, whereas endothelial-specific ATR1 deletion fully restored BBB integrity (Santisteban et al., 2020). This latter finding underscores the pivotal role of endothelial ATR1 in maintaining BBB structure and function.

ATR1-triggered oxidative stress and inflammatory pathways also contribute to Ang II-induced BBB impairment. Antioxidant treatments and pharmacological inhibition of T cell factor-β (TCF-β) or TLR4 have been shown to attenuate BBB dysfunction—including altered expression of TJPs and caveolin-1—following chronic infusion of Ang II (Atis et al., 2022; Mowry et al., 2021; Zhang et al., 2010). Chronic administration of Ang II has also been associated with increased microglial density, suggesting that ATR1 activation promotes TLR4 signaling, thereby enhancing neuroinflammation, immune cell recruitment, and BBB dysfunction (Foulquier et al., 2018). Consistent with this hypothesis, in vivo administration of TLR4 agonist disrupts BBB integrity through the downregulation of occludin and ICAM-1, which was reversed by ATR1 pharmacological blockade (Jang et al., 2020; Yang et al., 2021). In a pioneering in vitro study, decreased endothelial cell viability following treatment with either Ang II or LPS was accompanied by increased expression of TLR4, myeloid differentiation primary response (MyD)88, TNF-α, and caveolin-1 (Xia et al., 2022). These molecular changes were also coupled with heightened BSA-FITC leakage across the endothelial monolayer, all of which were prevented by TLR4 pharmacological inhibition of TLR4, highlighting the critical contribution of TLR4 signaling to ATR1-mediated modulation of BBB integrity (Xia et al., 2022).

The relationship between these upstream Ang II–mediated neurovascular dysfunctions and stress-associated phenotypes has been also described across psychiatric disorders. Elevated Ang II levels have been reported in patients with MDD, in parallel with increased circulating and CNS expression of inflammatory markers (Gong and Deng, 2023; Park et al., 2020). Ang II also promote the production of galectin-3, which can directly impair endothelial cells and exert depressant effects (Pang et al., 2023; Vargas et al., 2025). These findings altogether support a link between RAS overactivation, affective dysregulation, and the onset of depressive symptoms. ACE-dependent Ang II generation and ATR1 signaling have further been implicated in the exacerbation of depressive phenotypes. Genetic variants of the ACE gene—associated with increased enzymatic activity—correlate with enhanced hypothalamic–pituitary–adrenal (HPA) axis reactivity and increased vulnerability to MDD (Ali et al., 2023; Firouzabadi et al., 2012). Similarly, polymorphisms in the ATR1 gene have been linked to depression and to structural and functional alterations in fronto-limbic regions involved in emotion regulation, further supporting a pathogenic role for excessive ATR1 signaling in mood disorders (Taylor et al., 2012). The pathogenic influence of Ang II also extends to synaptic plasticity and oscillatory dynamics. Disruptions in theta–gamma oscillatory activity in the hippocampus and prefrontal cortex, coupled with microglia activation, have been shown to impair fear processing and promote anxiety like behavior (Gao et al., 2021; Park et al., 2020). Although research on RAS in bipolar disorder remains limited, clinical evidence indicates that circulating RAS components vary with mood states. Specifically, non-euthymic bipolar patients exhibit significantly reduced plasma ACE levels, suggesting that dysregulation of Ang II pathway contributes to bipolar disorder pathogenesis (Sanches et al., 2021).

Ang II–driven abnormalities further extend to PTSD, for which maladaptive threat learning and impaired fear extinction constitute core symptoms. Accumulating evidence indicates that Ang II signaling in the amygdala modulates these pathogenic learning processes. For instance, ATR1 deletion in the central amygdala enhances extinction learning, whereas stimulation of ATR2-expressing neurons dampens fear expression (Yu et al., 2019, 2023). In mice, exposure to repeated stress was sufficient to sensitize the Ang II system, as repeated traumatic stress enhances Ang II–dependent immune activation and vascular reactivity, thereby amplifying neuroinflammatory and autonomic responses that reinforce fear-related circuit dysfunction and promote persistent trauma-related behaviors (Case et al., 2025). Consistent with these findings, pharmacological blockade of Ang II–ATR1 signaling reverses traumatic stress-induced alterations. ATR1 antagonists such as losartan or candesartan facilitate fear extinction, reduce amygdala-driven fear expression, and normalize hippocampal–prefrontal network dynamics (Marvar et al., 2014; Shkreli et al., 2025; Swiercz et al., 2020). Clinically, individuals treated with Ang II receptor blockers display reduced PTSD symptom severity and a lower risk of developing PTSD following trauma compared with patients receiving other antihypertensive agents.

The anxiolytic and cognitive effects of ATR1 antagonism have been further demonstrated in randomized clinical trials. Oral administration of losartan induced an anxiolytic response and adaptive flexibility under looming-threat conditions (Han et al., 2025). However, another randomized controlled trial reported no significant effect of oral administration of losartan on task-switching, which was attributed to the ceiling performance among healthy controls (Prasad et al., 2025a). Notably, the same treatment regimen of losartan improved mnemonic discrimination—a function reflecting the ability to encode similar memories as distinct representations—which is frequently impaired in PTSD due to overlap between traumatic memories and safe experiences (Prasad et al., 2025b). Additional findings further demonstrated that losartan administration reduces aversive learning, attenuates anxiety-related symptoms, and decreases resting-state functional connectivity within memory-related networks—including the hippocampus, inferior frontal gyrus, and prefrontal cortex—areas critically implicated in the development of intrusive memory (Shkreli et al., 2024, 2025; Zika et al., 2024). Altogether, this body of evidence strongly supports a causal role for Ang II–ATR1 signaling in shaping vulnerability to trauma-related psychopathology (Kang et al., 2024; Seligowski et al., 2021a). Yet, how the BBB intervenes in the relationship between RAS and PTSD onset remains to be elucidated.

Although Ang II primarily contributes to BBB disruption through ATR1 activation, compensatory protective mechanisms involving ATR2 axis have been identified. ATR2 can modulate both the HPA axis and the sympathoadrenal system during stress, via lower catecholamine release and a blunted hormonal stress response (Saavedra and Armando, 2018). In line with these findings, Costa-Besada et al. reported that ATR2 signaling promotes NO production, limits oxidative stress, and reduces pro-inflammatory signaling (Costa-Besada et al., 2018). Such effects support BBB integrity and reduce neuroinflammation, which is particularly relevant stress-related neuropsychiatric conditions. Altogether, these studies indicate that ATR2 engage protective pathways both centrally and peripherally, counterbalancing ATR1–mediated neurovascular dysfunction under stress.

3. The implication of Ang II in BBB disruption in neurodegenerative diseases and brain injury

Over the past decade, clinical and preclinical evidence suggests that RAS-dependent neurovascular alterations contribute to the development of neurodegenerative diseases (Table 2). In rodent models of AD, Ang II actively contributes to the disruption of BBB integrity, thereby facilitating the entry of peripheral neurotoxic substances (e.g., β-amyloid peptides) into the brain parenchyma and accelerating neuro-degeneration (Li et al., 2016). Overactivated Ang II/ATR1 signaling also downregulates the expression of key endothelial TJPs (e.g., occludin and claudin-5), leading to BBB instability, accumulation of β-amyloid, and enhanced tau hyperphosphorylation (Lee et al., 2023). In addition, Ang II-driven activation of TLR4 promotes neuroinflammatory cascades known to exacerbate amyloid pathology and neuronal damage in AD brains (Biancardi et al., 2016). In an ovariectomized hyperlipidemic AD model, increased hippocampal concentrations of ACE1 accompanied with reduced ACE2 expression were associated with elevated calveolin-1levels and tau phosphorylation (Messiha et al., 2020). Pharmacological inhibition of ACE1 attenuated these AD-related alterations, highlighting that RAS-driven BBB disruption may result from the combined actions of Ang II and ACE1, the latter being critical for Ang I-to-Ang II conversion (Messiha et al., 2020).

Table 2.

The contribution of renin-angiotensin system and blood-brain barrier to neurodegenerative diseases

Species	Model/Condition	Findings	References
Human
Human	Alzheimer's Disease Dementia with Lewy bodies	↑ sICAM-1/sPECAM-1 in plasma and ↓ sVCAM-1 in CSF (vs controls)	Nielsen et al., 2007
Human	Parkinson's Disease – Long-term ARBs usage	Long-term ARBs use associated with ↓ risk of PD Prevention of BBB disruption Slower PD progression	Abo-Youssef et al., 2020; Jo et al., 2022; Lage et al., 2024
Rodents – Ethologically validated models
Aged rats	Postoperative cognitive dysfunction	↑ hippocampal levels of Ang II and AT1R, MMP/TIMP imbalance ↓ hippocampal expression of occludin and ZO-1; ↑Na—F and EB leakage in the hippocampus All these changes, except for ZO-1 were restored with AT1R blocker candesartan (0.1 mg/kg, IP for 14 days) No changes in serum levels of Ang (1–7) and Ang II ↑ Ang II levels and AT1R, MMP/TIMP imbalance	Li et al., 2014
			Li et al., 2016
Rat	Laparotomy-induced delayed neurocognitive recovery	↓ Ang-(1–7) in the hippocampus (up to 48 h later) ↑ MMP-9/TIMP imbalance and ↓ hippocampal levels of ZO-1 that were restored by the nonpeptide analog of Ang-(1–7) AVE 0991 (0.9 mg/kg; IN)	Mi et al., 2021
Mice	Vascular to cognitive impairment and dementia (VCID)-heart failure (HF)	Microglial activation and of 3 kDa/10 kDa dextrans leakage in CA1 and CA3 hippocampal regions	Hoyer-Kimura et al., 2024
Mice	Parkinson's Disease (PD) model with elevated Ang II levels	Ang II/AT1R overactivation in dopaminergic neurons and glial cells ↑ oxidative stress ↑ neuronal vulnerability ↑ α-synuclein aggregation BBB integrity disrupted	Lage et al., 2024
Rodents – Genetic lines
Mice	5XFAD Alzheimer model with chronic kidney disease	↑ whole brain and hippocampal IgG leakage that were restored with olmesartan (1 mg/kg/day, PO for 4 days)	Nakagawa et al., 2017
Rodents – Pharmacological models
Ovariectomized femelle rats	High-fat high fructose diet-induced hyperlipidemia in Alzheimer's Disease model	↑ ACE1 and ↓ ACE2 levels in the hippocampus ↑ calveolin-1 and p-tau in the hippocampus All these effects were improved by treatment with ACE1 inhibitor perindopril (0.5 mg/kg/day, PO for 30 days)	Messiha et al., 2020
In vitro
Endothelial cells	Brain microvascular endothelial cells exposed to Ang II	Overactivation of Ang II/AT1R signaling ↓ occludin and claudin-5 expression BBB instability ↑ β-amyloid accumulation ↑ tau hyperphosphorylation	Lee et al., 2023

ACE, angiotensin converting enzyme; Ang II, angiotensin II; ARB, angiotensin receptor blocker; ATR, angiotensin II receptor; BBB, blood-brain barrier; CSF, cerebrospinal fluid; EB, Evans blue; HRP, horseradish peroxidase; IN, intrana-sally; IP, intraperitoneally; MMP, matrix metalloproteinase; Na—F, sodium fluorescein; PO, per os; SC, subcutaneous; sICAM; soluble intercellular adhesion molecule-1; sPECAM, soluble platelet endothelial cell adhesion-1; sVCAM, soluble vascular adhesion molecule −1; TIMP, tissue inhibitors of metal-loproteinases; ZO, zonula occludens-1.

Additional preclinical studies have broadened our understanding of hippocampal neurovascular changes across various models of cognitive dysfunction. In rodent models, decreased hippocampal expression of TJPs occludin and ZO-1 correlated with elevated BBB leakage (Li et al., 2014, 2016). Cognitive dysfunction-associated increase in leakage of differently sized dextrans leakage in the CA1 and CA3 hippocampal regions was also accompanied with microglial activation (Hoyer-Kimura et al., 2024). In rats submitted to laparotomy-induced delayed neurocognitive recovery, MMP/TIMP imbalance occurred in parallel with increased Ang II and ATR1 expression and reduced levels of Ang (1–7) in the hippocampus (Mi et al., 2021). Interestingly, the latter Ang II/Ang (1–7) imbalance was not mirrored by changes in circulating levels of the same components, suggesting that brain-specific RAS signaling plays a primary role in BBB dysfunction in cognitive deficits (Mi et al., 2021). Nevertheless, an acute involvement of peripheral RAS cannot be excluded, and further studies need to better dissect peripheral vs CNS RAS mechanisms.

Ang II also contributes to the progression of PD by compromising BBB integrity. Elevated Ang II levels and ATR1 overactivation in dopaminergic neurons and glial cells are directly linked to oxidative stress, leading to neuronal vulnerability and promoting α-synuclein aggregation, a pathological hallmark of PD (Lage et al., 2024). BBB-penetrant angiotensin receptor blockers (ARBs) (i.e., telmisartan) have demonstrated neuroprotective effects in PD and AD models by mitigating Ang II-induced oxidative stress and preserving BBB integrity. At the clinical level, large multinational and longitudinal cohorts demonstrate that RAS-targeting antihypertensive agents are associated with slower AD progression and reduced dementia (Camacho-Meño et al., 2025; George et al., 2025; Jung et al., 2025; Sternberg et al., 2024). In particular, combined treatment with sacubitril and valsartan in heart-failure patients has been associated with a protective profile against cognitive decline (Jung et al., 2025). Overall, the literature supports an association between ARBs and reduced risk for PD and AD, reinforcing the therapeutic potential of RAS-modulated BBB stabilization in slowing neurodegenerative processes (Abo-Youssef et al., 2020; Jo et al., 2022; Lage et al., 2024).

Traumatic brain injury (TBI) has also been associated with BBB disruption. In a diffuse TBI rodent model, increased EB extravasation and oxidative stress were observed (Khaksari et al., 2018). In the controlled impact mouse model of TBI, reduced ZO-1 and occludin levels, as well as decreased aquaporin 4 polarity in the cortex were reported (Qian et al., 2024; Yang et al., 2023) (Table 3). BBB dysfunction was accompanied by increased cortical levels of neurodegenerative factors, such as amyloid precursor protein and Aβ1_40/42 (Yang et al., 2023), suggesting early neurodegenerative processes following TBI-induced neurovascular injury. Importantly, these BBB were only partially rescued by genetic or pharmacological deletion of ATR1, or pharmacological activation of ATR2 (Khaksari et al., 2018; Qian et al., 2024; Yang et al., 2023), indicating that the mechanical CNS injury may include additional pathways beyond RAS dysregulation in driving neurovascular pathology.

Table 3.

The contribution of renin-angiotensin system and blood-brain barrier in rodent models of traumatic brain injury

Species	Model/Condition	Findings	References
Rat	Diffuse TBI (dropped weight)	↑ EB leakage and oxidant index (MDA) in the brain These effects were attenuated by AT1R blocker candesartan (0.3 mg/kg; IP) ↑ brain edema and EB leakage; ↑ cerebral blood flow	Khaksari et al., 2018
Mice	Controlled cortical impact model of TBI	These effects were attenuated by selective nonpeptide ATR2 agonist C21 (0.03 mg/kg/day, IP for up to one month) ↑ brain infarction volume; ↑ EB leakage ↓ ZO-1 and occludin cortical levels; ↓ AQP4 polarity in the cortex ↑ APP, Aβ1–40 and Aβ1–42 cortical levels All the changes were partially rescued in AT1R-deficient mice	Qian et al., 2024
Mice			Yang et al., 2023

APP, amyloid precursor protein; AQP4, aquaporin 4; ATR, angiotensin receptor; EB, Evans blue; IP, intraperitoneally; MDA, malonedialdehyde; TBI, traumatic brain injury; ZO-1, zonula occludens-1.

4. Discussion

The available literature reinforces the key contribution of the RAS-regulated Ang II/ATR1 pathway to BBB disruption, ultimately promoting excessive hypertensive responses to stress, neurodegeneration, and brain injury. The reviewed evidence suggests that Ang II/ATR1 activation compromises the functionality of BBB endothelium via the loss of junctional elements—such as claudin-3/5, occludin, JAMs and ZO-1.

Stress, hypertension and neurovasculature:

In both humans and rodents, stress elicits acute or chronic, sustained hypertensive states (Manolis et al., 2025) that may differentially impact neurovascular integrity. A comparative study in borderline (i.e., stress-induced acute) and spontaneous hypertension rat models revealed BBB alterations only in spontaneously hypertensive rats (Şeren et al., 2024), suggesting that BBB vulnerability may require chronic RAS activation. In rats exposed to daily variable or repeated stress, cardiac parasympathetic activity was reduced, an effect reversed by ATR1 blockade (Costa-Ferreira et al., 2016). Interestingly, corticosterone increases following stress were un-affected by ATR1 blockade, suggesting that autonomic—but not HPA axis—changes are Ang II/ATR1-dependent (Costa-Ferreira et al., 2016). As chronic stress has been associated with infiltrating macrophages into brain tissue and BBB alterations in vivo (Dudek et al., 2020; Kokkosis et al., 2024), it may be hypothesized that the CNS responses are ATR1-independent, while the cardiovascular effects are ATR1-dependent.

In contrast, endothelial-specific ATR1 knockdown mitigated PTSD-like behaviors in a mouse model of acute, severe psychotrauma, in parallel with increased cortical expression of claudin-5 (Levesque et al. revision requested). These findings suggest that the type of stressor (acute vs chronic, psychological vs physiological) may shape distinct RAS-BBB interactions. Longitudinal studies are needed to better depict the causal relationship between acute vs chronic hypertension and BBB changes. Importantly, the contribution of TLR4-regulated neuroinflammation to ATR1-modulated neurovascular effects (Xia et al., 2022), and the abolished hypertension-related neurovascular alterations (Mowry et al., 2021) raise an important question: is there a direct crosstalk between ATR1-mediated signaling and TLR4-regulated neuroinflammatory pathways? Given that ATR1 activation promotes oxidative stress and NF-κB signaling, both of which are known upstream activators of TLR4, ATR1 signaling may sensitize or amplify TLR4 responses under pathological conditions.

Hypertension is a well-known risk factor for cognitive deficits in both humans (Abete et al., 2014) and rodents (Baggeroer et al., 2024). In animal models, chronic Ang II administration leads to short-term memory deficits along with increased cortical and hippocampal BBB permeability (Foulquier et al., 2018). BBB vulnerability may arise from peripheral RAS, central RAS, or their combined actions. Neurovascular alterations are consistently observed after following systemic RAS (i.e., administration of Ang II or L-supporting the role of peripheral RAS in BBB dysfunction. Conversely, hippocampal MMP/TIMP imbalance in mice presenting delayed neurocognitive recovery was not coupled with corresponding changes in circulating Ang II 48 h after brain injury (Mi et al., 2021). The latter finding emphasizes the importance of central RAS signaling in BBB dysfunction, but doesn't exclude the acute contribution of peripheral RAS at an earlier time point.

Ang II–mediated neurovascular dysfunction in stress-related psychiatric disorders:

Growing evidence positions Ang II–mediated neurovascular dysfunction as a unifying mechanism linking stress exposure to psychiatric vulnerability. By promoting neuroinflammation, endothelial impairment, HPA axis overdrive, or synaptic dysregulation, Ang II/AT₁R overactivation may bias the brain neural circuits toward maladaptive stress responses, potentially contributing to MDD, bipolar disorder, and PTSD. This perspective encourages a cross-disciplinary investigation of cardiovascular RAS modulators—such as ARBs and ACE inhibitors—as potential psychiatric interventions, given their ability to restore neuro-immune balance, vascular integrity, and synaptic plasticity. In parallel, circulating RAS markers (ACE, Ang II) may serve as diagnosis or predictive biomarkers of mood state or PTSD risk following traumatic stress. From a translational standpoint, these converging observations underscore the need for rigorous clinical trials of RAS-targeting agents in stress-related psychiatric disorders.

Cell- and region-specific actions of Ang II/ATR1 in CNS pathologies:

CNS expression of ATR1 is localized on glial (i.e., astrocytes and microglia) cells, endothelium, and neurons. Yet, available literature reporting the cell-specific role of ATR1 in neurological outcomes remains scarce (Li et al., 2024). Likewise, brain region-dependent actions of Ang II/ATR1 need to be further depicted. For instance, lentiviral ATR1a silencing in the central amygdala facilitated fear extinction (Yu et al., 2023), highlighting differential roles of ATR1 across hippocampal, cortical, and amygdalar circuits involved in cognition, psychiatric disorders, and brain injury (Rowe, 2010).

In a craniotomy-induced model of TBI, ATR1 antagonist candesartan improved functional outcomes and limited brain damage (i.e., microglial activation and infiltration of immune cells into the brain) in both young and aged mice (Timaru-Kast et al., 2019). In rodent models of LPS-induced neuroinflammation, prophylactic central perfusion of candesartan significantly decreased neuroinflammation, as observed with reduced levels of proinflammatory cytokines and adhesion molecules (Benicky et al., 2011). In a combined 5XFAD/chronic kidney disease mouse model, Ang II-driven oxidative stress caused hippocampal and cortical IgG leakage, which was fully reversed by a 4-day oral treatment with olmesartan (Nakagawa et al., 2017).

Despite robust preclinical evidence (Saavedra and Armando, 2018), clinical trials reported good but limited effects of acute treatment with ATR1 blockers in AD (Lee et al., 2023) and PTSD (Stein et al., 2021). These modest effects in humans may be attributed to several factors, including differences in disease stage when starting the treatment, heterogeneity of human symptomatology, and acute rather than chronic regimen. Combining approaches that simultaneously modulate ATR1 signaling and downstream inflammatory or oxidative pathways may enhance therapeutic efficacy by addressing multiple aspects of disease progression.

Sex- and gender-dependent incidence rates have been found across all neurological disorders, with women being more at risk for anxiety disorders, PTSD, MDD and dementia (Beam et al., 2018). Moreover, an observational study that included >116,000 patients with PTSD found that women were less responsive to ATR1 blockers (Seligowski et al., 2021a). In the available literature, only one study compared the sex effect on BBB leakage in mice with renin or angiotensinogen deficiency (Yanai et al., 2000). Future research must systematically incorporate sex—and gender in clinical settings— to identify distinct risk and treatment-response profiles.

In addition to regional and sex specificities, the behavioral dimension of Ang II/ATR1-mediated BBB alterations deserves consideration. Rodents exposed to chronic stress or Ang II-induced hypertension display anxiety-like behaviors, memory deficits, and impaired fear extinction (Dudek et al., 2020; Yu et al., 2023), paired with increased BBB permeability in stress-regulating brain regions (i.e., hippocampus, amygdala, and prefrontal cortex) (Foulquier et al., 2018; Hamasaki et al., 2020; Nagai et al., 2011; Yanai et al., 2000). For instance, endothelial-specific ATR1 deletion reversed cortical BBB disruption, and mitigated anxiety-like behaviors following acute psychotrauma (Levesque et al. revision requested). Likewise, lentiviral silencing of ATR1a in the central amygdala facilitated fear extinction performance (Yu et al., 2023). Despite these converging findings, the causal relationship between Ang II-induced BBB dysfunction and behavioral vulnerability remains to be fully elucidated. Integrated behavioral-neurovascular studies are needed for clarifying how RAS dysregulation contributes to the emergence of neuropsychiatric symptoms following stress.

Opposite contribution of Ang I/ATR2 to BBB function in brain disorders:

Although this review specifically focuses on Ang II, some of the cited studies also investigated Ang I/ATR2-mediated neurovascular protection. In rats, administration of Ang I or nonpeptide analog restored altered BBB integrity following ischemia (Wu et al., 2015) and delayed neurocognitive recovery (Mi et al., 2021). Ang I and its receptors ATR2 or MasR improved functional and cognitive recovery in a mouse model of TBI (Umschweif et al., 2014), and reduced LPS-induced microglia polarization in endothelial cells (Dang et al., 2021). ATR2 agonism also ameliorated functional and biological outcomes when administered early after stroke (McCarthy et al., 2012). In rodent models of TBI, both ATR1 blockade and ATR2 agonism partially reverted TBI-associated neurovascular alterations (Qian et al., 2024; Yang et al., 2023). This partial neurovascular restoration may be explained by the presence of irreversible CNS and neurovascular damages, reflecting the activation of additional signaling pathways beyond ATR1/ATR2 imbalance post-TBI.

Importantly, neuroprotective effects of ATR2 activation appears to be strongly time-dependent: delayed ATR2 agonism did not confer considerable neuroprotection when administered a long time after TBI (Timaru-Kast et al., 2019). To optimize the therapeutic and neuroprotective actions following TBI, ATR1 blockers or ACE inhibitors could be combined with statins (Li et al., 2020) or with an agonist of peroxisome proliferator-activated receptor-gamma (PPARɣ) (Villapol et al., 2012). PPARɣ appears to play a key role in ATR1 blockers' beneficial actions, as PPARɣ antagonist abolishes ATR1 blocker's benefits in a model of TBI (Villapol et al., 2015). Nevertheless, further work is required to gain a better understanding of the mechanisms underlying Ang I/ATR2-mediated BBB protection across CNS disorders and injury.

Neurodegenerative disorders show elevated incidence of psychiatric symptoms, including MDD and anxiety (Rabinowitz et al., 2015; Teng et al., 2008). The causal relationship between the incidence of some neurological symptoms and mental health issues is unclear, as psychiatric symptoms in these contexts may be explained by the interaction between disease-specific pathogenesis and limited quality of life. Un-fortunately, few studies examined RAS-BBB alterations in cognitive decline. For instance, Nielsen found no ACE changes in AD or Lewy body dementia despite altered levels of adhesion molecules (i.e., sICAM-1, sPECAM-1 and sVCAM-1) in plasma and cerebrospinal fluid (Nielsen et al., 2007). Given consistent neurovascular involvement in AD, TBI, and psychiatric disorders, it may be hypothesized that BBB disruption is a mechanistic bridge linking neurodegenerative and psychiatric symptoms. This perspective is supported by recent studies describing the altered TJPs as a hallmark feature of mood disorders (Greene et al., 2020), as well as the potential of clinical markers of BBB disruption as biomarkers (Futtrup et al., 2020).

In conclusion, we explored the preclinical and clinical evidence of the neuroprotective and deleterious impact of RAS on BBB integrity in stress-related disorders, neurodegenerative diseases, and TBI. The neurovascular effects of Ang II/ATR1 and Ang I/ATR2 pathways include modulated expression of endothelial adhesion molecules and TJPs, shaping BBB permeability. Despite promising preclinical support, clinical evidence remains mixed, limited by acute or single-dose treatment, sample heterogeneity, and insufficient sex balance. Future clinical trials should include sex parity, prioritize chronic treatment regimen, and identify the optimal therapeutic window. Overall, RAS represents a compelling but underexplored therapeutic target in neurological and psychiatric disorders. Clarifying its neurovascular actions will be essential for translating preclinical findings into effective clinical therapeutics.

Data availability

No data was used for the research described in the article.