Neurodegenerative Disorders in the Context of Vascular Changes after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) results from external biomechanical forces that cause structural and physiological disturbances in the brain, leading to neuronal, axonal, and vascular damage. TBIs are predominantly mild (65%), with moderate (10%) and severe (25%) cases also prevalent. TBI significantly impacts health, increasing the risk of neurodegenerative diseases such as dementia, post injury. The initial phase of TBI involves acute disruption of the blood–brain barrier (BBB) due to vascular shear stress, leading to ischemic damage and amyloid-beta accumulation. Among the acute cerebrovascular changes after trauma are early progressive hemorrhage, micro bleeding, coagulopathy, neurovascular unit (NVU) uncoupling, changes in the BBB, changes in cerebral blood flow (CBF), and cerebral edema. The secondary phase is characterized by metabolic dysregulation and inflammation, mediated by oxidative stress and reactive oxygen species (ROS), which contribute to further neurodegeneration. The cerebrovascular changes and neuroinflammation include excitotoxicity from elevated extracellular glutamate levels, coagulopathy, NVU, immune responses, and chronic vascular changes after TBI result in neurodegeneration. Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury. There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes. Also, the patterns of cerebrovascular dysfunction and stroke vulnerability after TBI are different in males and females based on animal studies.

1. Introduction

Traumatic brain injury (TBI) occurs when external biomechanical forces cause disturbances in the structure and physiology of the brain due to damage to the skull, leading to neuronal, axonal, and vascular injuries [1]. The majority of TBIs are categorized as mild (65%), with 10% classified as moderate and 25% as severe [2]. TBI has a huge health significance in societies and may increase the risk of neurodegenerative pathology by different mechanisms [3,4,5]. It can trigger dementia and lead to neurodegeneration [6,7]. Studies suggest a robust connection between developing neurodegenerative disorders and moderate to severe TBI, revealing a two to four times elevated risk of dementia. Moreover, experiencing a mild traumatic brain injury (MTBI) or another form of TBI can elevate the risk of developing dementia, persisting up to 30 years from the initial injury [8]. One cross-sectional analysis indicated that a history of TBI, even in the absence of loss of consciousness (LOC), is correlated with age-related neuropathological outcomes, having both neurodegenerative and vascular aspects [9]. Specifically, TBI with a LOC lasting more than 1 h was found to be associated with an elevated risk of cortical microinfarcts in studies such as the Religious Orders Study and Memory and Aging Project [10]. A recent meta-analysis revealed a 70% increased risk of dementia associated with TBI, especially in Asians and young men [11]. Another systematic review showed that there was evidence of dementia in TBI patients, reported in 15.5% of 44 published papers [12]. The triggering mechanisms for secondary neurodegeneration following TBI involve a sequence of interconnected pathological changes induced by the initial traumatic injury [1]. TBI can trigger acute disruption of the blood–brain barrier (BBB) through vascular shear stress, leading to both ischemic damage and the accumulation of Aβ [13,14]. The processes of hypoperfusion, vascular dysfunction, and ischemia following TBI may collectively contribute to Aβ deposition, playing a role in the secondary injury including endothelial cell dysfunction, cerebrovascular damage, oxidative stress, and mitochondrial damage [15].

Traumatic cerebrovascular injury is one of the most common abnormalities acutely reported in TBI patients [16]. Cerebral vascular dysfunction may occur before neuronal damage or develop as a consequence of neuronal dysfunction [17]. The cerebrovascular system’s pathology after TBI may originate from either direct injury to its components or as a result of a subsequent pathophysiological cascade triggered after the initial injury [17]. The dysfunction in blood vessel function seen immediately after the initial TBI persists for many months and years [18]. Further investigation is needed to explore the correlation between cerebrovascular pathology, neuroinflammation, and the severity of trauma [15].

The acute phase of TBI, typically described as the first week following injury, is characterized by predominant mechanical damage [19]. Initially, TBI disrupts the BBB, allowing activated leukocytes to migrate into the damaged brain tissue [19]. This mechanism is aided by the increased expression of cell adhesion molecules [19]. Macrophages become apparent immediately after the migration of polymorphonuclear leukocytes (PMNs), even though resident intracerebral macrophages (microglia) are uniformly distributed throughout the central nervous system [20]. Activated astrocytes, microglia, and leukocytes are recognized as sources of the pro-inflammatory cytokine response. They generate inflammatory molecules (e.g., cytokines and chemokines) and reactive oxygen species (ROS), which play a role in demyelination and the disturbance of the axonal cytoskeleton [19]. This disruption leads to axonal swelling and the buildup of transport proteins at the terminals, thus impairing the activity of neurons [19]. The ongoing axonal damage ultimately causes neurodegeneration [19]. Some of acute cerebrovascular changes after trauma are early progressive hemorrhage, micro bleeding, coagulopathy, neurovascular unit (NVU) uncoupling, changes in the BBB, changes in cerebral blood flow (CBF), and cerebral edema.

The secondary phase of injury, which can last months to years, is recognized by the delayed onset of metabolic dysregulation and inflammatory pathways [21,22,23]. Oxidative stress, which is characterized by ROS, seems to mediate the secondary phase of injury [24,25,26]. ROS are produced as a result of glutamate excitotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress [24,25,26]. ROS trigger lipid peroxidation and cause the disruption of the cell membrane; they also cause protein damage, which then leads to neurodegeneration and neuroinflammation [27]. The oxidative damage leads to an increase in pro-inflammatory cytokines (e.g., TNF-α, IL-1α, IL-1β, and IL-6) and causes further neurodegeneration [28]. TBI results in the cell accumulating Ca²⁺, which activates many widely distributed enzymes such as nitric oxide synthase, xanthine dehydrogenase, and phospholipase A2 that increase NO and O2 production [29]. The cascade can lead to structural changes in the membrane and in mitochondria, lipids, proteins, and DNA [30].

2. Excitotoxicity

Some studies have identified a number of cellular and molecular mechanisms that make a contribution to the development of cytotoxic and vasogenic edema, including the degradation of BBB components by matrix metalloproteinases, excitotoxicity due to excessive glutamate release, ion pump failure, mitochondrial dysfunction, the inflammation-induced release of vasoactive agents, the insertion of aquaporin 4 water channels into the cell membrane increasing the bi-directional flow of water driven by the net Starling force, and mechanical injury to the vasculature and tissue [31,32].

The extracellular accumulation of glutamate leads to an overstimulation of glutamate receptors, causing damage to both neurons and glial cells through excitotoxicity [33]. Increased levels of extracellular glutamate following TBI have been demonstrated to play a role in causing additional harm in experimental studies [34,35,36,37,38]. Recent research has shown a notable decrease in glial glutamate transporter proteins following experimental TBI, leading to elevated levels of extracellular glutamate [39,40,41]. Astrocytes play a key role in removing glutamate released at synapses through the primary mechanism of glutamate uptake [42,43]. A study showed that within the initial 24 h after TBI, the appearance of cells expressing the glutamate transporter at the site of contusion underwent morphological changes [44]. Numerous cells were massively swollen [44]. This morphology was also the most common during the 24 h to 7-day survival period [44]. In the later stages of survival, cells that were positive for excitatory amino acid transporters showed an increase in quantity and displayed characteristics such as highly stained, moderately branched processes and hypertrophic cytoplasm, resembling the appearance of reactive astrocytes [44]. After 7 days post injury, various astrocyte shapes were observed together at the contusion site [44]. The number of these cells was reduced significantly after three months post injury [44]. Astrocyte activation resulting from TBI is referred to as astrogliosis [45]. This phenomenon involves an atypical elevation in the quantity of astrocytes, changes in gene expression, alterations in morphology, and the formation of scar tissue [45]. Astrocytes exhibit signs of hypertrophy within 2 to 3 days following injury, and this hypertrophic state persists for up to 7 days post injury, concomitant with the formation of a glial scar [46]. Reactive astrogliosis has the capacity to persist for a duration of 60 days [46].

3. Coagulopathy and Hemorrhage

Patients who sustained a traumatic intracranial hemorrhage remained at risk for developing coagulopathy until 72 h after the trauma [47]. TBI coagulopathy is frequently broadly defined as any disturbance in a patient’s coagulation parameters [48]. Coagulopathy can emerge up to 5 days after injury, with its incidence showing a linear association with the severity of the injury [49]. The exact mechanisms responsible for coagulopathy in TBI have not yet been fully identified [50]. The coagulation pathway may result in disseminated intravascular coagulation (DIC) [50]. Patients with coagulopathy after TBI have poorer outcomes than others [51].

Early progressive hemorrhage occurs in approximately 50% of head-injured patients who undergo CT scanning within 2 h of injury; it occurs most frequently in cerebral contusions, and it is correlated with ICP elevations [52]. Microbleeds have been found in both the acute and chronic phases after TBI [53,54,55]. These accumulations of ferritin/hemosiderin are recognized to be harmful to endothelial cells and astrocytes [56,57], which can start cascades of inflammation. The cascades may involve the stimulation of gliosis and activation of apoptosis that have been linked to post-traumatic neurodegenerative outcomes [58]. Inflammation may persist for years following a single TBI [59]. Furthermore, microvascular abnormalities linked to axonal changes have been observed for up to 3 weeks following experimental TBI [60,61,62,63].

4. NVU Uncoupling

NVU is a vessel-centered concept, emphasizing that all cellular components play an integrated role in maintaining the normal physiological functions of the brain [64]. The neurovascular unit is formed by the neuron and its supporting cells, including astrocytes, endothelial cells, pericytes, and smooth muscle cells [65]. Their primary role is to provide various nutrients, including those required for nerve structure and distribution [64]. After brain injury, glial cells primarily regulate nerve repair factors and significantly contribute to the regeneration of both the central and peripheral nervous systems [66]. Their primary function involves integrating and interpreting signals released from adjacent cells, which leads to various functional outcomes such as modulating BBB permeability, promoting angiogenesis, eliminating toxic metabolites, regulating capillary blood flow dynamics, attenuating nerve inflammation, and modulating stem cell activity [67]. Hypoxia of the tissue frequently serves as the primary stimulus for a series of pathophysiological alterations within the NVU [68]. The changes following hypoxia include the disruption of interendothelial tight junctions, retraction of pericytes from the abluminal surface of the capillary, breakdown of the basal lamina with transudation of plasma, infiltration of inflammatory cells, endothelial cell proliferation and migration, and in some cases, vasculogenesis [68]. At the molecular level, this reorganization is accompanied by the increased expression of endothelial cell leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis [69]. NVU injury triggers the loss of BBB function and neurovascular uncoupling [68], marking the first pathological steps involved in initiating neurodegenerative cascades, and gradually lead to neurodegeneration [70].

5. BBB Disruption

The BBB is composed of the endothelial tight junction complex, which seals the intracellular space between endothelial cells and regulates transcellular transport [17]. One of the most serious outcomes of TBI is the disruption of the BBB, which varies according to patients’ age and the type and severity of the injury [71,72]. The immediate pathological change in the BBB following TBI is the disruption of its tight junctions, leading to an increase in paracellular permeability [73]. The extravasation of serum proteins such as fibrinogen and immunoglobulin G, both markers for BBB disruption, is observed in the brains of human patients who died in the acute phase following TBI, as well as in those who survived for at least 12 months [73].

The loss of pericytes is a key indicator of dysfunction in the BBB and has been proposed to initiate various pathological issues like abnormal BBB permeability, micro-aneurysm development, ischemia, and other related conditions [74,75]. It was shown that the initiation of oxidative stress triggers the activation of matrix metalloproteinases (MMPs), resulting in the breakdown of the BBB and the initiation of inflammatory responses after TBI [76,77]. Another research study showed that MMP-9 causes pericytes to move away from the endothelium, resulting in pericyte loss and disruption of the BBB [78]. PDGFR-β, αSMA (alpha-smooth muscle actin), NG2, CD13, and desmin are commonly used markers for pericytes [42,75,79,80]. PDGFR-β seems to be the most specific and is highly expressed in pericytes [81]. A study indicated that the levels of PDGFR-β, NG2, and CD13 were notably decreased after TBI [82]. However, the level of PDGFR-β expression decreased significantly at 12 h after TBI, then gradually increased at 24 h and 48 h, but did not reach the same level as in the uninjured samples [82]. The recruitment of CNS pericytes is dependent on the signaling of PDGF-B/PDGFR-β [83,84]. The PDGF-B secreted by endothelial cells binds to the PDGFR-β on pericytes, triggering various signaling pathways that control the growth, migration, and attraction of pericytes to the blood vessel wall [85,86]. Bhowmick et al.’s study indicated that the decrease in PDGFR-β expression on pericytes due to injury impacted the expression of PDGF-B on endothelial cells, leading to a disruption in PDGF-B/PDGFR-β signaling [82]. Also, they observed a decrease in the levels of N-cadherin and connexin-43 after TBI [82]. As pericytes and endothelial cells are linked through N-cadherin and connexin-43 in the neurovascular unit, the integrity of the BBB is clearly impacted by the absence of pericytes [82].

6. CBF Changes

Neuroimaging studies consistently demonstrate reduced CBF shortly after experimental TBI [17]. One study showed the changes in CBF in both cortical and subcortical regions using ASL-MRI, which may underlie deficits in cognitive function observed in MTBI patients during the acute stage [87]. In one study, it was demonstrated that patients whose CBF returns to normal levels at 2–3 weeks following traumatic brain injury, after being abnormally low in the acute phase of injury, can be expected to achieve a good neurological outcome [88].

Cerebral edema and the subsequent elevated ICP are linked to mortality and poor prognosis after TBI [89]. Increased ICP is linked to coma, brain herniation, and death [90]. Marmarou et al. [91] diagnosed that edema drives brain swelling in human TBI, as opposed to vascular engorgement and an increase in cerebral blood volume. Cerebrovascular injuries following TBI, including microbleeds and CBF dysfunction, contribute to poor outcomes and neurodegeneration [92].

7. Immune Reaction

Key contributors to the inflammatory response following brain injury include immune cells from the peripheral blood, such as neutrophils, as well as resident immune cells like macrophages and microglia [93,94,95,96,97]. All of these cells have the capability to generate pro-inflammatory substances, such as chemokines, the significant involvement of which in brain damage has been definitively demonstrated [98,99,100]. Resident microglia in the affected area and peripheral macrophages are promptly activated and migrate to the site of injury, where they begin to release signaling molecules and attract additional immune cells [101,102]. Distinguishing between the functions of resident microglia and infiltrating peripheral macrophages is a current focus of research [103]. This similarity complicates the differentiation of their respective roles in intracerebral inflammation [103]. The signature genes M1 (classically activated macrophage) and M2 (alternatively activated macrophage) are not exclusively expressed in microglia/macrophages, but also in other cells within the CNS or immune cells that have infiltrated the area [104]. A study showed that the presence of the M1 marker CD16/32 showed a slight increase in the cortex one day after TBI, and then significantly increased until day 14, and surprisingly, there were more CD16/32-positive microglia/macrophages in the opposite cortex three days after TBI compared to mice that underwent a sham operation [104]. Immunofluorescence for the M2 marker CD206 showed a notable increase above normal levels in the cortex and striatum on the same side as the injury three days after TBI [104]. The levels peaked on day 5 and then returned to baseline by day 14 [104]. These results show that there is a change over time in the type of microglial cells present after a mechanical injury, transitioning from a temporary M2 phenotype to a lasting M1 phenotype within a 14-day period [104]. The long-term impairment in myeloid and lymphocyte reactions following TBI indicates that TBI can lead to lasting changes in peripheral immune cell function [105]. The study revealed that there were notable deficiencies in the polarization of bone marrow-derived macrophages (BMDMs) obtained from mice with chronic TBI in comparison to BMDMs from sham control mice of equivalent time points [105]. Hence, BMDMs in mice with chronic TBI demonstrate permanent changes in the expression of inflammatory genes, potentially influenced by underlying epigenetic processes [105].

TBI triggers the activation of resident microglia, leading to the production of cytokines. This results in the entry of immune cells from the peripheral system, followed by a sustained activation of the brain’s resident microglia and astrocytes [93,106,107]. They are one of the initial groups to react to brain injury, and their continuous activation in animal models and individuals with TBI could play a role in causing long-term functional impairments [97,108,109,110,111]. Research conducted on spinal cord and ischemic brain injury models has revealed that most microglia and macrophages present at the injury site exhibit a combination of M1 and M2 activation characteristics [112,113]. However, the M2 response is temporary, and within a week of the injury, there is a transition towards a predominant M1-like response [112,113]. Furthermore, microglial cell phenotypes can vary based on tissue type, with a quicker shift from M2- to M1-dominant phenotypes observed in the white matter compared to the gray matter following TBI [104].

8. Chronic Vascular Changes after TBI

Angiogenesis is a key component of adult vascular remodeling and is facilitated by both mature endothelial cells and endothelial progenitor cells (EPCs) [114]. After TBI, EPCs can be found in the bone marrow and peripheral blood, from where they are moved to the peripheral blood [114]. After TBI, the number of CD34+ EPCs in peripheral blood increases at 24 h, peaks at 48 h, and returns to a normal level by 168 h [114]. As soon as 24 h after TBI, CD34+ cells can be identified in the area surrounding the damaged brain, and by 72 h after TBI, a CD34+ endothelial-like cell lining can be seen in the vessel-lumen structure [114]. The bone marrow-derived EPCs support endothelial repair and contribute to the formation of new blood vessels in ischemic conditions [115]. Vascular endothelial growth factor (VEGF) is recognized for its significant role in the process of angiogenesis [116]. Elevated levels of VEGFR1 and VEGFR2 were also observed in a cortical impact model of TBI [117].

9. Systemic Inflammation after TBI

Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes [118,119]. The effects of this extracranial multiorgan dysfunction on the brain include decreased cerebral blood flow, cerebral hypoxia, acidosis, altered metabolism, and bleeding. These factors can contribute to secondary brain injury and worsen clinical outcomes [118,119]. In addition to primary brain damage, secondary brain injuries worsen the outcomes of TBI [120,121]. The most common extracranial complications include multiple organ failure and infections [120,121]. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury [120]. Cardiac dysfunction is a reported consequence of TBI, particularly common in patients with more severe injuries, which causes hypotension, CBF changes, and secondary brain injuries [122,123]. Its hemodynamic and histologic profile suggests that sympathetic activation may be the underlying cause [120,124,125]. Recent studies have refined blood pressure thresholds for optimizing outcomes in severe TBI, considering age-dependent variations [120]. Significantly, cardiac dysfunction often develops shortly after the injury, a time when the injured brain is especially vulnerable to reduced cerebral blood flow [122]. However, cardiac function typically shows improvement during the first week of hospitalization after a traumatic brain injury [122]. Inappropriate activation of coagulation pathways may worsen organ dysfunction following severe TBI and is closely linked to negative outcomes, such as higher mortality rates, extended periods of mechanical ventilation, and increased functional disability [126,127,128]. Meta-analyses show that about one-third of TBI patients, particularly those with severe TBI, develop coagulopathy [129,130]. Ultimately, maladaptive coagulopathy manifests as DIC syndrome, resulting in microthrombosis, bleeding, and secondary brain injuries from both hemorrhagic and ischemic causes [131].

10. Sex Difference in TBI

There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes [132]. In TBI, extracerebral trauma may follow sex-specific patterns and lead to varying post-injury complications, which can result in different outcomes between sexes [132]. Women are more likely to experience injuries from assault or violence within interpersonal relationships, while men are more prone to work-related injuries due to falls and motor vehicle collisions [133,134,135]. Sex hormones and genetics probably impact edema, inflammation, excitotoxicity, oxidative stress, and mitochondrial function in both males and females following TBI [132]. Research also suggests that there are sex-based differences in recovery processes and brain repair, with varying levels of neuroplasticity observed between genders [132]. Given the current complex research on TBI in both males and females, it is not possible to definitively determine that one sex has better outcomes than the other [132,136]. The effect of sex hormones on vascular pathology after TBI has been studied in animal models. A study using a mouse model has demonstrated that following a mild TBI, male and female mice experience different patterns of cerebrovascular dysfunction and stroke vulnerability over time [137]. Sex differences in stroke vulnerability may partly result from previous brain injuries, which cause lasting changes in intravascular coagulation, blood–brain barrier permeability, and angiogenesis [137]. Another study using juvenile male mice demonstrated less acute inflammatory cytokine expression, greater subacute microglial/macrophage accumulation, and better neurological recovery compared to females, highlighting the importance of considering age and sex in TBI research to identify novel therapeutic targets [138]. In a rat model of TBI, male rats showed increased edema peaking at 5 h post injury, while female rats peaked at 24 h, with ovariectomized females displaying a profile similar to males. These differences suggest that endogenous hormone levels influence edema formation after TBI, potentially impacting clinical management [139].

Progesterone, a developmental hormone with neurosteroidal properties, has demonstrated neuroprotective and functional efficacy in numerous laboratories globally, across various animal models of TBI and stroke, leading to improved outcomes [140,141,142,143]. A study revealed that female rats in the proestrus stage of the estrous cycle (equivalent to the follicular phase in women) exhibit significantly smaller cortical contusion volumes compared to ovariectomized rats [144]. These proestrus rats also demonstrate a greater reduction in depression and show better behavioral outcomes following TBI [145]. In addition to research demonstrating the influence of estrous phases on TBI outcomes, studies have confirmed that TBI also disrupts estrous cyclicity in animal models, mirroring the post-injury menstrual disruption observed in women [146,147]. In experimental TBI models, post-injury estrous cyclicity is impaired, with animals spending more time in the diestrus phase (diestrus and metestrus are phases when progesterone levels peak) [146,147].

A meta-analysis of eight studies examining gender differences in TBI outcomes across all severity levels found that women had worse outcomes in 17 out of the 20 variables assessed [148]. Other studies have found that women, particularly those who are premenarchal or postmenopausal, tend to have better post-TBI outcomes compared to men [149,150]. These variables included postconcussive symptom scores, length of hospitalization, cognitive decline, depression, headache, return to work, reaction time compared to baseline, and death [151]. The phase of the menstrual cycle appears to be linked to quality of life and neurological outcomes after MTBI. Women who sustain an injury during the luteal phase, when progesterone levels are highest, experience worse outcomes compared to those in the follicular phase, when progesterone is low, or women taking synthetic progestins [152]. These findings seem to support the hypothesis that the acute withdrawal of progesterone following MTBI may play a role in the gender differences observed after the injury [151]. Conversely, a study found that women often miss menstrual periods or experience complete amenorrhea after TBI, indicating potential post-injury deficits in sex hormones [153]. Other studies have more conclusively demonstrated that TBI leads to the suppression of the hypothalamic–pituitary–gonadal axis, resulting in reduced levels of luteinizing hormone, follicle-stimulating hormone, testosterone, estrogen, and progesterone [154]. Although the preclinical documentation and multiple positive Phase II clinical trials were generally favorable, Phase III clinical trials revealed that progesterone was ineffective for patients with moderate to severe TBI [140].

11. Conclusions

TBI initiates a cascade of acute and chronic pathological processes, beginning with immediate mechanical damage and BBB disruption, followed by inflammation and neurodegeneration. The acute phase involves leukocyte migration into damaged brain tissue, releasing pro-inflammatory cytokines and ROS. The secondary phase extends over months to years, marked by oxidative stress, metabolic dysregulation, and continued inflammation. Elevated extracellular glutamate levels cause excitotoxicity, damaging neurons and glial cells. Coagulopathy and hemorrhage complicate recovery, with risks persisting up to 72 h post injury. NVU injury disrupts BBB integrity, leading to neurodegenerative cascades. Immune responses, including microglial activation and peripheral immune cell infiltration, play a significant role in sustaining inflammation and functional impairments. Chronic vascular changes, such as angiogenesis and endothelial repair, are crucial in the progression of TBI-induced neurodegeneration. Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury. There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes. Also, the patterns of cerebrovascular dysfunction and stroke vulnerability after TBI are different in males and females based on animal studies. A comprehensive understanding of these mechanisms is essential for developing targeted interventions to mitigate long-term effects and improve outcomes for TBI patients. As a future direction, controlling the vascular component of systemic inflammation and understanding organ cross-talk post-TBI could address the broader impacts on patient health. Also, it might be helpful to examine the role of estrogen in protecting against vascular changes after TBI.