Background: Patients with spinal cord injuries (SCIs) are at a greater risk for the development of cardiovascular diseases (CVDs) than able-bodied individuals due to the high risk of endothelial dysfunction. Summary: For instance, patients with SCIs lose autonomic control of the heart and vasculature, which results in severe fluctuations in blood pressure. These oscillations between hypotension and hypertension have been shown to damage blood vessel endothelial cells and may contribute to the development of atherosclerosis. Furthermore, the loss of skeletal muscle control results in skeletal muscle atrophy and inward remodeling of the conduit arteries. It has been shown that blood vessels in the legs are chronically exposed to high shear, while the aorta experiences chronically low shear. These alterations to shear forces may adversely impact endothelial vasodilatory capacity and promote inflammatory signaling and leukocyte adherence. Additionally, microvascular endothelial vasodilatory capacity is impaired in patients with an SCI, and this may precede changes in conduit artery endothelial function. Finally, due to immobility and a loss of skeletal muscle mass, patients with SCIs have a higher risk of metabolic disorders, inflammation, and oxidative stress. Key Messages: Collectively, these factors may impair endothelium-dependent vasodilatory capacity, promote leukocyte adhesion and infiltration, promote the peroxidation of lipids, and ultimately support the development of atherosclerosis. Therefore, future interventions to prevent CVDs in patients with SCIs should focus on the management of endothelial health to prevent endothelial dysfunction and atherosclerosis.

The incidence of spinal cord injuries (SCIs) in the USA increases by >17,000 cases annually [1]. Importantly, more than 70% of new SCIs occur in younger adults (15–40 years of age) [2]. However, despite their younger age, the incidences of cardiovascular diseases (CVDs), including ischemic heart disease [3‒5], stroke [6], and peripheral artery disease [7], are elevated among patients with SCIs. Unfortunately, the precise mechanisms underlying the elevated CVD burden in those with SCIs are unclear, which hinders the development of evidence-based interventions to prevent CVDs in this population. Therefore, understanding the pathophysiological links between SCIs and CVDs is an important next step to produce clinical interventions that prevent CVDs in patients with SCIs and ultimately extend their lifespans.

Several direct and indirect consequences of SCIs may negatively affect cardiovascular function and promote the development of CVDs. Of note, partial or complete severing of the spinal cord impairs both the autonomic and somatic nervous systems [8]. Therefore, SCIs cause autonomic dysregulation of the heart and vasculature [9], which impairs the control of hemodynamics [10]. Furthermore, somatic impairments lead to large volumes of skeletal muscle being unusable [8]. This indirectly reduces skeletal muscle metabolic rate [11], increases skeletal muscle atrophy [12], promotes remodeling of the vasculature [13], and promotes metabolic syndrome [14‒16], thereby leading to increases in central adiposity [17], proinflammatory cytokines [18‒20], oxidative stress [21, 22], dyslipidemia [15], and insulin resistance [16]. Therefore, SCIs present a complex integration of hemodynamic and metabolic insults to cardiovascular function that may independently or synergistically lead to the development of CVDs.

Although apparently complex, an underlying commonality linking these SCI-mediated factors to the development of CVDs may be their negative influences on the vascular endothelium, which is integrally responsible for regulating communication within the cardiovascular system and for maintaining adequate oxygen and nutrient availability to peripheral tissues and organs [23]. Under healthy physiological conditions, the endothelium is in a quiescent state and protects against the development of atherosclerosis [24]. However, the cardio-metabolic insults attributed to SCIs may promote a pro-atherosclerotic endothelium, characterized by increased vascular inflammation, permeability, and leukocyte adhesion, thereby leading to vascular dysfunction and atherosclerosis [23, 24]. Therefore, the purpose of this mini-review is to elucidate SCI-mediated mechanisms contributing to endothelial dysfunction to reveal the targets for future interventions to prevent CVDs in patients with SCIs.

The vascular endothelium is a single-cell monolayer that lines the entire interior of the vasculature, from the conduit arteries to the microvasculature. The endothelium is in direct contact with both the blood and underlying smooth muscle and plays a critical role in transducing mechanical and chemical stimuli from the blood into biochemical signals for the regulation of vascular smooth muscle tone [23]. Importantly, vascular smooth muscle tone is continuously modulated to maintain proper perfusion and oxygen delivery to peripheral tissues in alignment with their metabolic demands. One of the most notorious endothelial-derived vasodilatory factors is nitric oxide (NO), which is a gaseous molecule produced from l-arginine by endothelial nitric oxide synthase (eNOS) [25]. NO produced in the endothelium diffuses across the basolateral membrane into the underlying smooth muscle, where NO activates soluble guanylyl cyclase, leading to an increase in cyclic guanosine monophosphate and phosphorylation of myosin light chain phosphatase, which inhibits the phosphorylation of myosin light chain and ultimately prevents actin and myosin cross-bridge formation, leading to a loss of smooth muscle tension and vasorelaxation [25]. Of note, the endothelium also produces vasoconstrictor molecules, such as endothelin-1, which increases smooth muscle intracellular calcium, leading to the phosphorylation of myosin light chain and ultimately the development of smooth muscle tension and vasoconstriction [26]. Furthermore, the endothelium is responsive to many extrinsic vasoactive substances such as angiotensin II, norepinephrine, acetylcholine, and cytokines that promote vasodilation and vasoconstriction. Importantly, it is the balance of vasoactive substances that determines the net vasomotor tone on the vasculature.

One of the most important external stimuli that dictates vasomotor tone, and the internal environment of the endothelium, is shear stress [23, 27]. The endothelium is rich in mechano-transducers that are sensitive to the direction and intensity of shear forces from the movement of blood [23, 28‒31]. Importantly, antegrade shear forces from laminar flow stimulate the production of NO through eNOS [27, 32]. Furthermore, laminar flow is known to increase nuclear translocation of nuclear factor erythroid 2-related factor (Nrf2) and promote the transcription of antioxidant protein mRNA [33, 34]. Additionally, laminar flow downregulates pro-inflammatory signaling within the endothelium by reducing activation of the transcription factors activator protein 1 (AP-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) [35], which reduces subsequent production of endothelial cytokines and adhesion molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 (VCAM-1) [23, 36, 37]. Therefore, laminar flow promotes an anti-atherosclerotic endothelium that encourages vasodilation and prevents vascular inflammation and oxidative stress [27]. On the contrary, oscillatory shear forces (i.e., oscillating antegrade retrograde shear forces) and chaotic shear forces from turbulent flow are known to increase the production of endothelin-1 [38] and superoxide anion [39], which can scavenge NO to peroxynitrite [40] and ultimately decrease NO bioavailability. Furthermore, these adverse shear patterns are known to decrease Nrf2 translocation and promote vascular inflammation through AP-1 and NFκB, thereby promoting leukocyte adhesion by intercellular adhesion molecule 1 and VCAM-1 [41]. Therefore, oscillatory and chaotic shear stresses promote “endothelial activation,” which is a pro-atherosclerotic endothelium that encourages vasoconstriction, vascular inflammation, oxidative stress, and ultimately atherosclerosis [23]. Importantly, SCIs result in several vascular and metabolic adaptations that may promote endothelial activation and the development of atherosclerosis.

Immediately after sustaining an SCI, autonomic communication to the vasculature and heart is disrupted. The severity of autonomic dysfunction is related to the level of injury to the spinal cord, where an injury at or below T1 results in a loss of sympathetic innervation to the heart and vasculature of the upper and lower body, and an injury below T5 results in a loss of sympathetic innervation to the lower body [8, 9]. Loss of sympathetic control of the heart and vasculature ultimately interferes with proper blood pressure regulation and results in periods of severe orthostatic hypotension (systolic blood pressures <50 mm Hg) and periods of autonomic dysreflexia with severe hypertension (systolic blood pressures >300 mm Hg) that can occur up to 40 times per day [8, 42, 43]. These severe fluctuations in blood pressure result in under- and over-perfusion of the microvasculature and peripheral tissues [44] and may lead to pro-atherosclerotic shear patterns on the endothelium, thereby promoting endothelial dysfunction. Indeed, recent evidence from Philips et al. [44] and Sachdeva et al. [45] in mouse models of SCI suggests that repeated exposures to severe blood pressure fluctuations result in reduced carbachol-mediated vasodilation in cerebral arteries. Carbachol is an acetylcholine mimetic that activates muscarinic receptors to increase endothelium intracellular calcium and NO production through eNOS [46]. Therefore, reduced carbachol-mediated vasodilation may indicate impaired NO bioavailability in endothelial cells after repeated exposures to SCI-mediated blood pressure fluctuations. Furthermore, Sachdeva et al. [45] reported that chronic exposure to autonomic dysreflexia has been associated with reduced endothelial expression of platelet endothelial cell adhesion molecule 1 and transient receptor potential vanilloid 4 [45], which may decrease endothelial sensitivity to fluid shear forces. Additionally, SCI-mediated fluctuations in blood pressure have been shown to increase collagen deposition within the vasculature and reduce vascular distensibility, thereby further contributing to impaired vasodilatory capacity [44, 45]. It is well established that the vasculature changes intraluminal diameter to maintain equilibrium between shear forces and transmural pressure [47], so a loss in vasodilatory capacity may ultimately result in an impaired ability to regulate shear forces and pressure. Therefore, severe fluctuations in blood pressure due to autonomic dysreflexia may ultimately contribute to the development of endothelial dysfunction in those with SCIs.

In addition to causing adverse fluctuations in blood pressure, autonomic dysreflexia can also promote dangerous cardiac arrhythmias such as atrial fibrillation (AF) in those with SCIs [48, 49]. Importantly, AF may reduce blood flow and shear stress in the peripheral vasculature [50], thereby further contributing to SCI-mediated endothelial dysfunction. Indeed, markers of endothelial dysfunction such as asymmetric dimethylarginine, symmetric dimethylarginine [51‒54], and von Willebrand factor are all elevated in those with AF [55]. Furthermore, those with AF have reduced eNOS expression [56], NO bioavailability [56], and brachial artery flow-mediated dilation (FMD) [57, 58]. Interestingly, FMD is improved after AF is resolved, which is further evidence that AF contributes to endothelial dysfunction [59]. Therefore, AF from autonomic dysreflexia may be an important contributing factor to SCI-mediated endothelial dysfunction. Overall, current evidence indicates that chronic exposures to SCI-mediated fluctuations in blood pressure result in adverse shear patterns on the endothelium that may promote an activated endothelium with reduced sensitivity to shear and reduced NO bioavailability. However, direct measurements in those with SCIs are currently lacking and represent an important area of future research.

In addition to causing autonomic dysregulation, SCIs also result in somatic nerve system impairments below the level of injury [9]. This ultimately inhibits conscious control of large volumes of skeletal muscle. The loss of conscious skeletal muscle contractions results in skeletal muscle atrophy [12], reduced skeletal muscle mitochondrial content [60], and reduced skeletal muscle metabolism [11]. Due to a lack of metabolic demand below the SCI, upstream conduit arteries are remodeled. Previous studies suggest that the superficial femoral arteries (SFAs), common femoral arteries, and popliteal arteries are all reduced in diameter after an SCI [61‒65] in proportion to the loss of distal muscle mass [13, 61]. Furthermore, SFA stiffness is increased due to a higher wall-to-lumen ratio [66]. Interestingly, it has been reported that leg blood flow is not impaired following an SCI [61‒63], but antegrade shear stress in the leg arteries is highly elevated [61‒63], likely due to reduced intraluminal diameters. Current evidence on whether endothelial dysfunction exists in leg arteries exposed to chronically high shear after an SCI is equivocal.

The most common method to assess leg conduit artery endothelial function in patients with an SCI has been the assessment of conduit artery vasodilation in response to an increase in shear using the FMD technique [67], which has been considered an assessment of endothelial NO-dependent vasodilation [64]. Of note, De Groot et al. [62] found that SFA shear stress and relative FMD were higher in SCI than in able-bodied controls. However, when corrected for the shear stimulus, there were no differences in FMD in patients with an SCI. Furthermore, relative nitroglycerin-mediated vasodilation was not different between patients with an SCI and able-bodied controls, thereby indicating that SFA smooth muscle function is not impaired in SCI [62]. In alignment, de Groot et al. [61] reported that SFA absolute and relative FMD increases during the first 6 weeks after an SCI in parallel to decreases in SFA intraluminal diameter and increases in shear stress. However, when corrected for the changes in shear stress, there were no changes in SFA FMD. Furthermore, Kooijman et al. [64] reported that SFA FMD is higher in patients with SCIs compared to able-bodied controls. Additionally, after administration of the eNOS inhibitor, NG-monomethyl-l-arginine, SFA FMD was considerably reduced in SCIs, thereby providing evidence that the SFA FMD response is primarily mediated by NO in patients with an SCI. Recently, Coombs et al. [63] reported that unnormalized and shear-normalized SFA FMD were not different between patients with an SCI and able-bodied individuals. Furthermore, Totosy de Zepetnek et al. [65] found that despite SFA shear being higher in SCI compared to able-bodied individuals, SFA FMD was not different in patients with an SCI. In contrast, Stoner et al. [68] reported that posterior tibial artery FMD was reduced in patients with an SCI compared to able-bodied controls. Furthermore, in contradiction to De Groot et al. [61] the physiological range of intraluminal diameters achieved during the FMD test was blunted in patients with an SCI compared to able-bodied individuals [68]. However, this contradiction may be partially explained by the larger posterior tibial artery diameters reported in patients with SCIs compared to able-bodied controls [68], since relative FMD is known to be lower in arteries with larger diameters [69].

Overall, previous evidence supports that shear-normalized SFA FMD is not reduced in SCI [61‒64], so endothelial sensitivity to a change in shear may be preserved. However, it is not known whether the chronically high stimulus for NO production due to elevated shear stresses is sustainable across the lifespan [61‒63]. Interestingly, it is well established in able-bodied individuals that NO bioavailability decreases with age [70‒72]. Therefore, it is possible that in patients with SCIs, arteries exposed to tonically high shear may experience symptoms of impaired NO bioavailability at a younger age compared to arteries exposed to normal shear stresses because of a larger demand for NO at rest, i.e., arteries experiencing high shear in patients with SCIs may experience accelerated aging compared to those in able-bodied individuals. Interestingly, the lower ankle-brachial index reported in patients with SCI compared to age-matched able-bodied individuals may be evidence for accelerated arterial aging and atherosclerosis in patients with an SCI [73].

It should also be appreciated that not all arteries experience elevated shear forces because of an SCI. Of note, Yeung et al. [74] reported that after an SCI, the distal aorta is chronically distended, has lower wall shear stress, and is more prone to aneurisms compared to able-bodied individuals. This maladaptation may be in response to augmented resistance in the leg arteries due to inward vascular remodeling [61‒65]. Indeed, there is a reduced pressure decay during diastole in the distal aorta in patients with an SCI [74], which may be explained by concomitant changes in aortic elastic properties and increases in peripheral vascular resistance. Ultimately, with reductions in aortic wall shear stresses, patients with SCIs may be more susceptible to endothelial dysfunction in the distal aorta and the development of atherosclerosis.

While the incidence of macrovascular endothelial dysfunction in patients with an SCI may be unclear, current literature supports that microvascular endothelial dysfunction may be prevalent in SCIs. Previous literature has demonstrated that after a period of leg arterial occlusion, there is less reactive hyperemia in the legs of patients with SCIs compared to able-bodied individuals [62‒64], thereby indicating impaired microvascular vasodilatory capacity. Furthermore, it has been reported in the arms and legs of patients with SCIs that the plateau in cutaneous vascular conductance during local heating is blunted [75]. Since the plateau in cutaneous vascular conductance during local heating is primarily mediated by NO [76], this indicates that NO bioavailability may be impaired in the microvasculature of those with an SCI. Interestingly, Thijssen et al. [77] reported that endothelin-1 sensitivity may be higher in patients with an SCI [77], and Wang et al. [18] reported that serum endothelin-1 is higher in SCIs [18], so endothelin-1 may directly oppose the actions of NO in the microvasculature. Furthermore, Coombs et al. [63] provided evidence for microvascular endothelial activation, since serum CD62e+ (a marker of endothelial activation) was elevated in those with SCI, which paralleled a reduction in reactive hyperemia while SFA FMD was preserved. Overall, current evidence indicates that microvascular endothelial dysfunction may precede the development of macrovascular endothelial dysfunction in those with an SCI. Interestingly, this aligns with trends in able-bodied individuals, demonstrating that microvascular dysfunction precedes symptomatic macrovascular dysfunction and CVDs [78‒89]. Therefore, biomarkers of microvascular endothelial dysfunction should be explored in those with SCIs for the early detection of CVD development.

As previously discussed, SCIs cause both autonomic and somatic nervous system dysfunctions, leading to vascular dysfunction and a loss of conscious control of large volumes of skeletal muscle. Due to these impairments, it has been reported that those with an SCI are not physically active [90, 91] and have an attenuated resting metabolic rate compared to able-bodied individuals [92]. Furthermore, SCI-mediated sympathetic dysfunction interferes with leptin [93] and hepatic signaling [94], thereby impairing satiety signaling and hepatic metabolic functions, respectively. Overall, these SCI-mediated dysfunctions heighten the risk of developing metabolic disorders, inflammation, and oxidative stress. Importantly, it has been reported that those with SCIs have greater incidences of central adiposity [17], insulin resistance [16], dyslipidemia [15], and impaired antioxidant capacity [21, 22]. Higher central adiposity in those with an SCI may be associated with increased proinflammatory cytokines and NFκB signaling [20]. Indeed, Wang et al. [18] reported that those with SCIs have elevated levels of C-reactive protein, interleukin-6, and sVCAM-1 compared to able-bodied individuals. Importantly, these factors may contribute to endothelial activation and leukocyte adhesion, which is an essential step in the development of atherosclerosis [95]. Furthermore, the combination of impaired antioxidant capacity [21, 22] and dyslipidemia [15] may make those with an SCI highly susceptible to lipid peroxidation, another important step in the development of atherosclerosis [96]. Indeed, Savikj et al. [21] reported elevated levels of 4-hydroxynonenal (a marker of lipid peroxidation) in those with an SCI compared to able-bodied individuals. Finally, SCI-mediated insulin resistance and impaired antioxidant capacity may contribute to the impaired NO bioavailability observed in the microvasculature of those with an SCI [75]. Overall, metabolic dysfunction, low-grade inflammation, and oxidative stress in those with an SCI may contribute to a pro-atherosclerotic endothelium with decreased NO bioavailability, increased leukocyte adhesion, and increased permeability. Future investigations are warranted to determine if exercise and behavioral interventions can effectively protect endothelial function from the metabolic abnormalities present in those with SCIs.

The loss of control of the autonomic and somatic nervous systems after an SCI initiates and promotes vascular and metabolic adaptations that may lead to a pro-atherosclerotic endothelium and CVDs. Autonomic dysregulation of the heart and vasculature causes severe fluctuations in blood pressure that may deleteriously affect endothelium-produced NO bioavailability. Additionally, blood flow shear patterns on the endothelium may become adverse after an SCI due to reductions in leg macrovascular intraluminal diameter and increases in aortic distensibility. Furthermore, microvascular NO bioavailability may be impaired after an SCI, and microvascular endothelial dysfunction may attenuate leg skeletal muscle circulatory function. Finally, due to immobility, loss of skeletal muscle mass, and lower metabolic rate and resting energy expenditure, patients with an SCI exist in a state of low-grade inflammation with increased cytokine signaling, impaired redox balance, and insulin resistance that may ultimately reduce endothelium NO bioavailability, increase inflammatory leukocyte adhesion, and increase endothelium permeability. Overall, several important factors contribute to endothelial dysfunction in patients with SCI and may explain the greater incidence of CVDs in this population. Therefore, future research and interventions aimed at reducing CVDs in those with SCIs should focus on the management of endothelial health to prevent endothelial maladaptation and subsequent atherosclerosis.

No conflicts of interest, financial or otherwise, are declared by the authors.

This study was not supported by a sponsor or funder.

A.B.-A., C.P.A., and S.-Y.P. drafted the manuscript. A.B.-A., C.P.A., M.J., S.-S.P., G.L., and S.-Y.P. edited and revised the manuscript. A.B.-A., M.J., and S.-S.P. prepared and revised the graphical abstract. A.B.-A., C.P.A., M.J., S.-S.P., G.L., and S.-Y.P. approved the final version of the manuscript.

Additional Information

Andres Benitez-Albiter and Cody P. Anderson contributed equally to this work.

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