Stretch-Induced Intimal Failure in Isolated Cerebral Arteries as a Function of Development.

Recent clinical studies have shown that traumatic brain injury is a significant risk factor for stroke. Motivated to better understand possible mechanisms of this association, we studied subfailure disruption of the intima in overstretched sheep cerebral arteries, as this has been implicated in the increased risk of stroke following blunt cerebrovascular injury. Middle cerebral arteries from four age groups (ranging from fetal to adult) were stretched axially to failure, and intimal disruption was captured with a video camera. All vessels demonstrated intimal disruption prior to catastrophic failure, with nearly all incurring disruption at stretch values well below those at ultimate stress (means of 1.56 and 1.73, respectively); the lowest stretch associated with intimal disruption was 1.29. The threshold of intimal failure was independent of age. Additional analysis showed that disruption included failure of both the endothelium and internal elastic lamina. Although our experiments were conducted at quasi-static rates, the results likely have important implications for vessel function following trauma. Future work should seek to identify subfailure disruption of the cerebrovasculature in head trauma.

The effect of coarctation degrees on wall shear stress indices.

Coarctation of the aorta (CoA) is a congenital tightening of the proximal descending aorta. Flow quantification can be immensely valuable for an early and accurate diagnosis. However, there is a lack of appropriate diagnostic approaches for a variety of cardiovascular diseases, such as CoA. An accurate understanding of the disease depends on measurements of the global haemodynamics (criteria for heart function) and also the local haemodynamics (detailed data on the dynamics of blood flow). Playing a significant role in clinical processes, wall shear stress (WSS) cannot be measured clinically; thus, computation tools are needed to give an insight into this crucial haemodynamic parameter. In the present study, in order to enable the progress of non-invasive approaches that quantify global and local haemodynamics for different CoA severities, innovative computational blueprint simulations that include fluid-solid interaction models are developed. Since there is no clear approach for managing the CoA regarding its severity, this study proposes the use of WSS indices and pressure gradient to better establish a framework for treatment procedures in CoA patients with different severities. This provides a platform for improving CoA therapy on a patient-specific level, in which physicians can perform treatment methods based on WSS indices on top of using a mere experience. Results show how severe CoA affects the aorta in comparison to the milder cases, which can give the medical community valuable information before and after any intervention.

Simple model of atherosclerosis in cylindrical arteries: impact of anisotropic growth on Glagov remodeling.

In 1987, Seymour Glagov observed that arteries went through a two-stage remodeling process as a result of plaque growth: first, a compensatory phase where the lumen area remains approximately constant and second, an encroachment phase where the lumen area decreases over time. In this paper, we investigate the effect of growth anisotropy on Glagov remodeling in five different cases: pure radial, pure circumferential, pure axial, isotropic and general anisotropic growth where the elements of the growth tensor are chosen to minimize the total energy. We suggest that the nature of anisotropy is inclined towards the growth direction that requires the least amount of energy. Our framework is the theory of morphoelasticity on an axisymmetric arterial domain. For each case, we explore their specific effect on the Glagov curves. For the latter two cases, we also provide the changes in collagen fiber orientation and length in the intima, media and adventitia. In addition, we compare the total energy produced by growth in radial, circumferential and axial direction and deduce that using a radially dominant anisotropic growth leads to lower strain energy than isotropic growth.

Tunica intima compensation for reduced stiffness of the tunica media in aging renal arteries as measured with scanning acoustic microscopy.

OBJECTIVES: Aging causes stiffness and decreased function of the renal artery (RA). Histological study with light microscopy can reveal microscopic structural remodeling but no functional changes. The present study aimed to clarify the association between structural and functional aging of the RA through the use of scanning acoustic microscopy. METHODS: Formalin-fixed, paraffin-embedded cross-sections of renal arteries from 64 autopsy cases were examined. Speed-of-sound (SOS) values of three layers, which correspond to the stiffness, were compared among different age groups. SOS of the tunica media was examined in terms of blood pressure (BP) and SOS of the ascending aorta. Vulnerability to proteases was assessed by SOS reduction after collagenase treatment. RESULTS: The tunica intima presented inward hypertrophy with luminal narrowing, and the tunica media showed outward hypertrophic remodeling with aging. SOS of the tunica media and internal and external elastic laminae showed a reverse correlation with age. SOS of the tunica media was negatively correlated with BP and strongly associated with that of the aorta. The tunica media of young RAs were more sensitive to collagenase compared with the old ones. CONCLUSIONS: Scanning acoustic microscopy is useful for observing the aging process of the RA. This technique simultaneously shows structural and mechanical information from each portion of the RA. In the process of aging, the RA loses contractile function and elasticity as a result of protease digestion. The tunica media and the internal and external elastic laminae exhibit reduced stiffness, but the tunica intima stiffens with atherosclerosis. As a consequence, the RA's outer shape changes from round to oval with inward and outward hypertrophy. This indicates that the inner resistant intima supports the mechanical weakness of the tunica media to compensate for an increase in BP with aging.

Acute Myocardial Infarction in an Adolescent Receiving Anagrelide for Essential Thrombocythemia with Underlying Persistent Coronary Endothelial Dysfunction.

Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked increase in the numbers of mature megakaryocytes present in the bone marrow. Thrombohemorrhagic disorders are major morbidities of ET, especially those with mutations in the gene encoding Janus kinase 2 (JAK2). In this study, we report the case of an 18-year-old patient with ET carrying JAK2 mutation who developed acute ST-elevation myocardial infarction (STEMI) 5 months after a commencement of anagrelide. Coronary endothelial dysfunction confirmed by positive acetylcholine provocation test lasted a year after the occurrence of STEMI. Furthermore, intracoronary imaging using optical coherence tomography demonstrated non-atheromatous intimal fibrosis possibly due to chronic endothelial damage. The coronary pathologies reflected chronic change potentially associated with properties of ET and JAK2 mutation in addition to hyperviscosity. These observations suggest that the side effect of anagrelide in our patient was considered causative, while underlying chronic endothelial dysfunction and adverse endothelial remodeling may be predisposing factors to his fatal cardiovascular events.

Hemodynamic and Histopathological Changes in the Early Phase of the Development of an Intracranial Aneurysm.

Hemodynamic stress and chronic inflammation are closely associated with the pathogenesis of intracranial aneurysms (IAs). However, the hemodynamic and biological mechanisms triggering IA formation remain to be elucidated. To clarify them, computational fluid dynamics (CFD) and histopathological analyses in the early phase of IA development using an experimentally induced IA model in rats were conducted. Histological changes in the early phase of IA development were observed under a scanning electron microscope (SEM) and a transmission electron microscope (TEM). Using data from 7-T magnetic resonance angiography (7T-MRA), CFD analyses were performed to determine wall shear stress (WSS) and wall pressure (WP) at the prospective site of IA. A bump-like protrusion named an "intimal pad" was located in the anterior cerebral artery (ACA) immediately distal to the apex of the bifurcation. TEM showed the degeneration of the internal elastic lamina (IEL) and longitudinally elongated smooth muscle cells (SMCs) that switched from the contractile to the proliferative phenotype and penetrated between two divided layers of the degenerated IEL in the prospective site of the IA. However, no inflammatory cells were observed. CFD analyses showed no particular pattern of WSS and WP at the prospective IA site. IEL degeneration and the phenotypic change and longitudinal elongation of SMCs were identified as the early events in IA development. CFD analyses and TEM data suggest that these biological events may be derived from increased circumferential wall stress due to increased blood pressure and increased longitudinal wall strain due to the existence of the intimal pad.

A Rabbit Venous Interposition Model Mimicking Revascularization Surgery using Vein Grafts to Assess Intimal Hyperplasia under Arterial Blood Pressure.

Although vein grafts have been commonly used as autologous grafts in revascularization surgeries for ischemic diseases, the long-term patency remains poor because of the acceleration of intimal hyperplasia due to the exposure to arterial blood pressure. The present protocol is designed for the establishment of experimental venous intimal hyperplasia by interposing rabbit jugular veins to the ipsilateral carotid arteries. The protocol does not require surgical procedures deep in the body trunk and the extent of the incision is limited, which is less invasive for the animals, allowing long-term observation after implantation. This simple procedure enables researchers to investigate strategies to attenuate the progression of intimal hyperplasia of the implanted vein grafts. Using this protocol, we reported the effects transduction of microRNA-145 (miR-145), which is known to control the phenotype of vascular smooth muscle cells (VSMCs) from the proliferative to the contractile state, into harvested vein grafts. We confirmed the attenuation of intimal hyperplasia of vein grafts by transducing miR-145 before implantation surgery through the phenotype change of the VSMCs. Here we report a less invasive experimental platform to investigate the strategies that can be used to attenuate intimal hyperplasia of vein grafts in revascularization surgeries.

Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator.

This review seeks to provide an update of preclinical findings and available clinical data on the chronic persistent inflammation and its direct role on the pulmonary arterial hypertension (PAH) progression. We reviewed the different mechanisms by which the inflammatory and immune pathways contribute to the structural and functional changes occurring in the three vascular compartments: the tunica intima, tunica media, and tunica adventitia. We also discussed how these inflammatory mediator changes may serve as a biomarker of the PAH progression and summarize unanswered questions and opportunities for future studies in this area.

Venous intima-media thickness increases both in deep and superficial systems in patients with great saphenous vein reflux.

OBJECTIVE: To evaluate by Doppler ultrasound (DUS) the venous intima-media thickness (vIMT) in patients with or without great saphenous vein (GSV) incompetence. METHODS: A prospective vIMT measurement was performed by DUS in an outpatient cohort. Patients were divided in two groups: group A, patients without GSV reflux; and group B, patients with at least one refluxing GSV. Group B was further divided in group B1, patients with monolateral refluxing GSV; and group B2, patients with bilateral GSV reflux. The vIMT was measured in the femoral vein (FV), 3 to 5 cm distal to the saphenofemoral junction (vIMT[FV]), and in the GSV, 3 to 5 cm from saphenofemoral junction (vIMT[R-] or vIMT[R+]) in the case of a nonrefluxing or a refluxing GSV, respectively. Only one limb per patient was considered for vIMT analysis: in group A, the limb with the greater vIMT(R-), in subgroup B1 the limb with a refluxing GSV, and in subgroup B2 the limb with the lower vIMT(R+). The primary outcome was the difference of vIMT of GSV between groups A and B. Secondary outcomes were differences in vIMT(FV) among groups and the correlation between vIMT of GSV and demographic or clinical parameters. A subgroup analysis of vIMT in GSV was conducted in B1 patients, describing vIMT variations in both limbs. RESULTS: Forty-four patients were enrolled. In the group A (26 patients), vIMT of the GSV was lower than in the group B (18 patients; 0.31 ± 0.01 mm vs 0.49 ± 0.02 mm; P < .001). The difference was significant also for vIMT(FV) (group A, 0.67 ± 0.02 mm vs group B, 0.77 ± 0.03 mm; P < .014). No statistical correlation between age, body mass index, family history, or use of elastic stockings and vIMT(FV) or vIMT(R+ or R-) was detected. Considering the whole population, vIMT of GSV was higher in patients with Clinical, Etiology, Anatomy and Pathophysiology (CEAP) class C of 2 or greater than in classes C 0 and 1 (0.43 ± 0.02 mm vs 0.32 ± 0.02 mm; P < .0002). The difference was significant also for vIMT(FV) in patients with class a class C of 2 or greater and C of 0 to 1 (0.77 ± 0.02 mm vs 0.64 ± 0.03 mm; P < .0008, respectively). In group B1, vIMT(R+) was higher than vIMT(R-) (0.50 ± 0.02 mm vs 0.32 ± 0.02 mm, respectively; P < .0001). The difference was not significant for vIMT(FV). CONCLUSIONS: vIMT seems to be an indirect marker of saphenous insufficiency. In GSV incompetence, an augmented wall thickening is visible in the FV as well. Further studies are needed to assess the accuracy of DUS measurements of vIMT. Longitudinal studies are also needed to evaluate possible GSV and FV vIMT variations related to disease progression or treatment.

Association between acute aortic dissection and the distribution of aortic calcification.

OBJECTIVE: Aortic calcification (AC) is associated with increased risks of cardiovascular events and mortality. Numerous studies have explored the association between calcification and abdominal artery aneurysm. However, evidence regarding the association between AC and acute aortic dissection (AAD) is limited. We aimed to evaluate the association between AC-related variables and the development of intimal tear (IT) in patients with AAD. METHODS: We conducted a retrospective observational study involving 64 patients with type A AAD and 32 patients with type B AAD from February, 2011 to January, 2017 at a tertiary referral medical center in Taiwan. We used the default analysis module "calcification score analysis" to calculate all the calcification variables, including AC scores and volume. RESULTS: We identified an association between AC and AAD. Patients with AAD had a greater AC volume in the aortic arch and greater AC scores for both the ascending aorta and the aortic arch than did patients without AAD. However, hypertension and coronary artery disease, rather than AC remained to be the independent risk factor for AAD in multivariate analysis. Patients with type A AAD had greater mean and cumulative AC volumes in the aortic arch, greater cumulative AC volumes in the whole aorta and higher cumulative AC scores in the aortic arch than did patients with type B AAD. ACs were superimposed on ITs in nearly half of the patients with AAD. In patients with type A AAD, AC was more commonly located distal to the IT and farther from the IT. CONCLUSIONS: We identified the associations between AC-related variables and the location of IT in patients with AAD. However, AC was not an independent risk factor for AAD. The distribution of AC was different between patients with type A and type B AAD.

Anisotropic fractional viscoelastic constitutive models for human descending thoracic aortas.

The generalized fractional Maxwell model, formulated for hyperelastic material within the framework of the nonlinear viscoelasticity with internal variables, is applied to identify viscoelastic constitutive equations from layer-specific experimental data obtained by uniaxial harmonic loading of ex-vivo human descending thoracic aortas. The constitutive parameters are identified by using a genetic algorithm for the optimal fitting of the experimental data. The accuracy of the fitted fractional model is compared to the fitted integer order model with the same number of Maxwell elements. The formulation of an original strain energy density function for anisotropic nonlinear viscoelasticity is introduced and constitutive parameters are obtained from the experiments.

Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury.

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

Nonthrombotic proliferative vasculopathy associated with antiphospholipid antibodies: A case report and literature review.

A 20-year-old man presented with recurrent hemoptysis for seven months. A small subpleural nodule in his right lower lobe was found and excised surgically. Based on the presence of antiphospholipid antibodies (aPL) and vascular wall hypertrophy without vasculitis or an intraluminal thrombus, nonthrombotic proliferative vasculopathy (NTPV) affecting pulmonary arteries was diagnosed. Recently, aPL have been postulated to directly induce the proliferation of vascular cells in the intima and media, leading to NTPV. We review 5 cases of NTPV-associated aPL with critical ischemia in the lower extremities and gastrointestinal infarction. NTPV-associated aPL might be distinct from classic antiphospholipid syndrome and should be considered in aPL-positive patients who present with vascular occlusions of medium-sized vessels in the absence of atherosclerotic risk factors and systemic or local inflammation.

Media sclerosis drives and localizes atherosclerosis in peripheral arteries.

Media sclerosis (MS) and peripheral artery disease (PAD) may coincide, particularly in type 2 diabetics (T2D) and in patients with chronic kidney disease (CKD). In contrast to non-diabetics, in T2D PAD is more severe and more distal. Although MS is suspected to play a role, the underlying pathophysiological reasons for the differences still remain elusive today. We tested the hypothesis that MS is a promoter of atherosclerosis as it occurs in T2D with PAD by interfering with arterial remodeling using an in-silico simulation. We confirmed that MS aggravates PAD by promoting negative remodeling. We found that the effect is more pronounced in smaller distal arteries compared to larger proximal ones. Our results suggest that the degree of this divergence depends on the ratio between the thickness of the intima relative to the thickness of the media/adventitia of the individually affected arteries.

Application of medical adhesive inhibits intimal hyperplasia involving the downregulation of ERK1/2 and eNOS levels.

Vein graft remains the most broadly applied vascular material in coronary artery bypass surgery. However, the restenosis rate of the vein bridge following angioplasty is high. The present study investigated the effect of medical adhesive on vascular intimal hyperplasia, in addition to the signal transduction mechanism. A total of 36 New Zealand white rabbits were divided into three groups at random, including the normal group, the surgery group and the medical adhesive spray group. Following surgery for transplantation of the left external jugular vein to the ipsilateral common carotid artery for 4 weeks, the thickness and area of the intima and media of the vessel were measured on formalin­fixed, paraffin wax­embedded pathological sections using hematoxylin­eosin staining, and alterations in the expression of proliferating cell nuclear antigen (PCNA), platelet endothelial cell adhesion molecule 1 (PECAM­1), vascular cell adhesion protein 1 (VCAM­1), extracellular signal­regulated kinase (ERK)1/2, and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemical staining, reverse transcription­quantitative polymerase chain reaction analysis and western blotting. The levels of intimal hyperplasia in the medical adhesive spray group were markedly decreased compared with the surgery group. Consistently, PCNA, PECAM­1 and VCAM­1 were underexpressed in the medical adhesive spray group compared with the surgery group. ERK1/2 and eNOS were underexpressed in the medical adhesive spray group compared with the surgery group. Therefore, the application of medical adhesive may inhibit intimal hyperplasia, which may be associated with the restriction of the over­distension of the vein graft by downregulating the ERK1/2 and eNOS levels, reducing injury to the vascular intima and inhibiting the signaling pathway involved in intimal hyperplasia.

Difference Between Persistent Aneurysm, Regressed Aneurysm, and Coronary Dilation in Kawasaki Disease: An Optical Coherence Tomography Study.

BACKGROUND: Coronary artery (CA) aneurysms are a serious complication of Kawasaki disease (KD). Conventional imaging techniques often described segments with regressed aneurysms as normal, whereas studies have shown significant endothelial dysfunction. METHODS: KD patients with aneurysms scheduled for routine coronary angiography underwent optical coherence tomography (OCT) imaging between 2013 and 2016. Microstructural coronary changes were compared between normal CA segments and those with dilation, regressed aneurysms, and persistent aneurysms. RESULTS: OCT was performed on 33 patients aged 12.0 ± 5.4 years, 8.5 ± 5.4 years after KD diagnosis. Of the 79 segments analyzed, 25 had persistent aneurysms, 22 regressed aneurysms, 11 CA dilation, and 21 no CA involvement. Intimal thickness was 489 ± 173 µm, 304 ± 158 µm, 102 ± 68 µm, and 63 ± 29 µm, respectively (P < 0.001). There was a linear correlation between the maximum aneurysm size and the intimal thickness, as well as coronary dimension at the time of OCT. Fibrosis (54 segments, 68%) and cellular infiltration (22 segments, 28%) were found more often in segments with CA involvement, but also those without (P = 0.01; P = 0.02). Destruction of the media (34 segments, 43%), calcifications (6 segments, 8%), neovascularization (18 segments, 23%), and white thrombi (8 segments, 10%) were found almost exclusively in segments with a history of aneurysms. CONCLUSIONS: Intimal hyperplasia, fibrosis, and cellular infiltration were found in all categories of CA involvement, whereas calcification, destruction of the media, neovascularization, and white thrombi were found essentially only in segments with saccular or fusiform aneurysms. Prospective studies with outcome correlations are needed to see if this is associated with an increased risk of late adverse events.

A New Technique to Induce Experimental Myointimal Hyperplasia.

BACKGROUND: Arterial myointimal hyperplasia (MIH) has a significant impact on the long-term outcomes of vascular procedures such as bypass surgery and angioplasty. In this study, we describe a new and innovative technique to induce MIH using a dental flossing cachet in Wistar rats. METHODS: The intimal damage in the common carotid artery was induced by inserting the tip of the dental flossing cachet through the external carotid artery into the common carotid artery and turning it on for 3 rounds of 20 s each (n = 10). After 2 weeks, the rats were anesthetized and the common carotid arteries of the experimental side and the contralateral side (control) were harvested and preserved for histopathological studies. RESULTS: The experimental carotid arteries showed significant intimal proliferation and thickening compared to the controls. The intima/media ratio of the experimental and normal (control) common carotid arteries were 1.274 ± 0.162 and 0.089 ± 0.023 (mean ± SEM), respectively (p < 0.001). CONCLUSION: This technique is simple, inexpensive, and highly reproducible and it induces sufficient MIH to study this phenomenon in animal models.

The polymorphism rs6918289 located in the downstream region of the TREM2 gene is associated with TNF-α levels and IMT-F.

Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response, and influences negatively on TNF-α expression levels. Genetic epidemiology studies have identified polymorphisms located in the TREM2 gene associated with neurodegenerative and chronic inflammatory diseases. TREM2 levels have been observed to affect plasma levels of TNF-α and plaque stability in symptomatic and asymptomatic patients with carotid stenosis. In this study, we investigated polymorphisms located in the TREM2 gene region and association with TNF-α levels and the intima media thickness of the femoral artery. The discovery population from the STANISLAS Family Study comprised of 809 individuals, whereas the replication population utilized an independent cohort of French origin (n = 916). Our results suggest that the minor allele (T) of SNP rs6918289 is positively associated with elevated plasma levels of TNF-α in discovery and replication populations (P = 0.0026, SE = 0.04 and P = 0.023, SE = 0.09, respectively), including femoral artery thickness in the discovery cohort (P = 0.026, SE = 0.009). Results indicate that rs6918289 may be considered as a risk factor for inflammatory diseases and could be used in stratified medicine with patients diagnosed with chronic inflammatory-related conditions, such as atherosclerosis.

Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall.

Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted.

The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.

Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal thickening throughout the arterial tree, fibronectin and collagen deposition, and collagen cross-linking. We then address the most common in vivo and in vitro models used to gain mechanistic insight into the consequences of intimal remodeling. Finally, we consider the impacts of intimal stiffening upon endothelial cell mechanotransduction with emphasis on the emerging impact of increased complexity in cellular traction forces and substrate rigidity upon endothelial barrier integrity.