Arterial Blood Vessels Research Articles

Warfarin Accelerates Ectopic Mineralization in Abcc6−/− Mice: Clinical Relevance to Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. Warfarin, a commonly used anticoagulant, is associated with increased mineralization of the arterial blood vessels and cardiac valves. We hypothesized that warfarin may accelerate ectopic tissue mineralization in PXE, with clinical consequences. To test this hypothesis, we developed a model in which Abcc6(-/-) mice, which recapitulate features of PXE, were fed a diet supplemented with warfarin and vitamin K1. Warfarin action was confirmed by significantly increased serum levels of oxidized vitamin K. For mice placed on a warfarin-containing diet, quantitative chemical and morphometric analyses revealed massive accumulation of mineral deposits in a number of tissues. Mice fed a warfarin-containing diet were also shown to have abundant uncarboxylated form of matrix Gla protein, which allowed progressive tissue mineralization to ensue. To explore the clinical relevance of these findings, 1747 patients with PXE from the approximately 4000 patients in the PXE International database were surveyed about the use of warfarin. Of the 539 respondents, 2.6% reported past orpresent use of warfarin. Based on the prevalence of PXE (approximately 1:50,000), thousands of patients with PXE worldwide may be at risk for worsening of PXE as a result of warfarin therapy.

Yellow papules: the iceberg of systemic elastorrhexis

Systemic elastorrhexis is a multisystem genetic disorder characterised by dystrophic mineralization of soft connective tissues in a number of organs, including the skin, the eyes and the arterial blood vessels. Although the eye and skin findings have for years attracted the attention of ophthalmologists and dermatologists, the systemic nature of the disorder has not received sufficient attention among internists and many patients with this disorder have undoubtedly been unrecognized. We reported a case of systemic elastorrhexis redressing the diagnosis of vascular leucoencephalopathy of an unknown aetiology for many years.

Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy

SUMMARYGeneralized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis – those mice developed stiffening of the joints, hence the mutant mouse was named ‘ages with stiffened joints’ (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI.

Pattern of fetal arterial blood flow in selected vessels in patients with pregnancy induced hypertension in Aminu Kano Teaching Hospital Kano, Nigeria

Background: Doppler velocimetry of fetal arterial blood flow in pregnancy induced hypertension (PIH) determines fetal hemodynamic adjustment. Objective: This study was aimed to determine the pattern of fetal arterial blood flow of selected vessels in patients with PIH. Materials and Methods: A total of 34 pregnant women with PIH at a gestational age of 24-37 weeks were prospectively examined with Doppler ultrasound of the fetal middle cerebral artery (MCA), umbilical artery and placental blood flow (uterine artery). Results: The mean peak systolic velocity (PSV) of the fetal MCA was 8.23±3.96, resistance index (RI) was 0.763±0.07 and systolic diastolic (S/D) ratio was 4.558±1.36. The mean PSV of umbilical artery was 72.28±26.585, RI was 0.62±0.19 and S/D was 2.63±0.75. The mean placental blood flow (uterine artery) PSV was 141.34±70.58, RI was 0.59 and S/D was 2.42±1.07. Uterine artery PSV was normal in only six patients. Uterine artery was also not sonographically demonstrated in two patients. Conclusion: Doppler velocimetry of arterial blood vessels in pregnancy complicated with PIH reveals abnormal pattern; its application in PIH would be useful for further management.

The complexity of elastic fibre biogenesis in the skin – a perspective to the clinical heterogeneity of cutis laxa

Elastic fibres are critical connective tissue components providing elasticity and resilience to skin and other tissues. These fibres are composed of elastin and a number of elastin-associated microfibrillar proteins that assemble in a complex fibre network in a multi-step process. Multiple cellular processes, including mitochondrial function, specific molecules in the secretory pathways and temporally and spatially ordered production of elastic fibre components, are required for the biogenesis of functional elastic fibres. Abnormalities in these processes can lead to loss of functional elastic fibres manifesting phenotypically as a skin disease. The paradigm of elastic fibre diseases affecting the skin is cutis laxa, a clinically and genetically heterogeneous group of disorders characterized by loose and sagging skin, frequently associated with extracutaneous manifestations in the lungs and the arterial blood vessels. The complexity of cutis laxa is emphasized by the fact that as many as 10 distinct genes can harbour mutations in this and related disorders. Understanding of the pathomechanistic pathways involved in perturbed elastic fibre assembly in cutis laxa provides information potentially helpful for the development of molecular strategies towards treatment of these, currently intractable, diseases.

P2Y Purinoceptors as Potential Emerging Therapeutical Target in Vascular Disease

In the last two decades a tremendous development has been noticed in our understanding of the purinergic system, consisting of heterogeneously expressed purinoceptor subtypes and its classical agonists: e.g., adenosine triphosphate, uridine triphosphate or complex dinucleoside polyphosphates. These agonists exert multiple effects on the vascular system: they regulate the relaxation and constriction of arterial blood vessels, lead to proliferation and migration in endothelial cells and vascular smooth muscle cells, and mediate potent proinflammatory responses or phenotypic cell changes. This review focuses on the P2 purinoceptor subtype P2Y and its pleiotropic effects in the vascular wall under physiological and pathophysiological condition. Various experimental and clinical studies provide evidence that pharmacological targeting of P2Y might be effective in reducing vascular alterations under disease conditions.

Bioactivation of nitroglycerin is determined by the subcellular localization of aldehyde dehydrogenase-2

Objective In the present study we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells with selective overexpression of the enzyme in either cytosol or mitochondria. Furthermore we investigated a potential correlation between the relaxation potency of GTN and the distribution of ALDH2 in arterial blood vessels from different species as well as the subcellular distribution of the enzyme in several murine organs.

Shear-stress sensitive lenticular vesicles for targeted drug delivery

Atherosclerosis results in the narrowing of arterial blood vessels and this causes significant changes in the endogenous shear stress between healthy and constricted arteries. Nanocontainers that can release drugs locally with such rheological changes can be very useful. Here, we show that vesicles made from an artificial 1,3-diaminophospholipid are stable under static conditions but release their contents at elevated shear stress. These vesicles have a lenticular morphology, which potentially leads to instabilities along their equator. Using a model cardiovascular system based on polymer tubes and an external pump to represent shear stress in healthy and constricted vessels of the heart, we show that drugs preferentially release from the vesicles in constricted vessels that have high shear stress.

2278 RE-ENDOTHELIALIZATION OF ACELLULAR KIDNEY SCAFFOLDS FOR WHOLE ORGAN ENGINEERING

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Vascular Surgery II1 Apr 20122278 RE-ENDOTHELIALIZATION OF ACELLULAR KIDNEY SCAFFOLDS FOR WHOLE ORGAN ENGINEERING In Kap Ko, Sayed Hadi Mirmalek Sani, Shay Soker, Tamer Aboushwareb, Anthony Atala, and James Yoo In Kap KoIn Kap Ko Winston Salem, NC More articles by this author , Sayed Hadi Mirmalek SaniSayed Hadi Mirmalek Sani Winston Salem, NC More articles by this author , Shay SokerShay Soker Winston Salem, NC More articles by this author , Tamer AboushwarebTamer Aboushwareb Winston Salem, NC More articles by this author , Anthony AtalaAnthony Atala Winston Salem, NC More articles by this author , and James YooJames Yoo Winston Salem, NC More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2456AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The lack of transplantable allografts for renal failure has prompted the development of scaffold design and cell isolation techniques in order to re-create an engineered whole kidney. Decellularized solid organ xenografts such as the kidney hold great promise due to the maintenance of structural integrity while removing all cellular components. However, acelluar kidney vasculature needs an endothelial cell lining to avoid blood clotting and thrombus formation when transplanted into a living recipient. In order to maintain blood circulation and induce renal functions, re-endothelialization of acellular scaffold is critical. METHODS In this study, we describe an endothelial cell seeding method that permits effective endothelial cell coating on the vascular walls of the decellularized porcine kidney scaffolds. We conducted MS1 endothelial cell seeding of acellular porcine renal scaffold using a combination method (static and ramping perfusion method). RESULTS We showed that combined MS1 seeding facilitated well-organized endothelium on the decellularized blood vessels, confirmed by H&E staining and SEM analysis. Organized endothelial cells were shown on the artery, vein, and smaller blood vessels without apparent clogging of cells at the capillary structures in the cortex. Vascular tree imaging demonstrated that the endothelium on the arterial system of the kidney is well preserved and covered with viable endothelial cells, confirmed by GFP expression on continuous arterial branches of the entire kidney. Furthermore, MS1 seeded scaffold displayed significant inhibition of platelet adhesion on cell-attached surfaces as compared to the strong platelets deposition found on the unseeded scaffolds. CONCLUSIONS Using a combined static and ramping perfusion seeding method proved to be a viable method for endothelial cells seeding. Future work will be aimed at improving cell adhesion as well as increasing cell numbers. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e919 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information In Kap Ko Winston Salem, NC More articles by this author Sayed Hadi Mirmalek Sani Winston Salem, NC More articles by this author Shay Soker Winston Salem, NC More articles by this author Tamer Aboushwareb Winston Salem, NC More articles by this author Anthony Atala Winston Salem, NC More articles by this author James Yoo Winston Salem, NC More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Highly flexible capacitive strain gauge for continuous long-term blood pressure monitoring

An innovative procedure for measuring blood pressure, with none of the disadvantages of current procedures, is proposed. A highly-flexible capacitive strain gauge has been designed to measure changes in the diameter of a blood vessel; such changes are indicative of blood pressure. The sensor is implanted and wrapped around an arterial blood vessel during the normal course of a surgical procedure. In vivo tests, demonstrating the feasibility of this concept, are reported, along with in vitro tests and notes on sensor design and fabrication. These continuous blood pressure monitoring sensors may be used for a continuous long-term monitoring of blood pressure and pulse. They may also be combined with a real-time nerve stimulation technique or a course of medication to create a closed-loop system for blood-pressure control.

Role of shear-stress-induced VEGF expression in endothelial cell survival

Vascular endothelial growth factor (VEGF) plays a crucial role in developmental and pathological angiogenesis. Expression of VEGF in quiescent adult tissue suggests a potential role in the maintenance of mature blood vessels. We demonstrate, using a Vegf-lacZ reporter mouse model, that VEGF is expressed by arterial but not by venous or capillary endothelial cells (ECs) in vivo. Using an in vitro model, we show that arterial shear stress of human umbilical vein ECs (HUVECs) decreases apoptosis and increases VEGF expression, which is mediated by the induction of Krüppel-like factor 2 (KLF2). Additionally, shear stress stimulates the expression of VEGF receptor 2 (VEGFR2) and is associated with its activation. Knockdown of VEGF in shear stressed HUVECs blocks the protective effect of shear stress, resulting in EC apoptosis equivalent to that in control ECs cultured under static conditions. Similarly, treatment of ECs subjected to arterial shear stress with the VEGF receptor tyrosine kinase inhibitor SU1498, or VEGFR2 neutralizing antiserum, led to increased apoptosis, demonstrating that the mechanoprotection from increased shear is mediated by VEGFR2. Taken together, these studies suggest that arterial flow induces VEGF-VEGFR2 autocrine-juxtacrine signaling, which is a previously unidentified mechanism for vascular EC survival in adult arterial blood vessels.

Computational Simulation of Hematocrit Effects on Arterial Gas Embolism Dynamics

Recent computational investigations have shed light into the various hydrodynamic mechanisms at play during arterial gas embolism that may result in endothelial cell (EC) injury. Other recent studies have suggested that variations in hematocrit level may play an important role in determining the severity of neurological complications due to decompression sickness associated with gas embolism. To develop a comprehensive picture, we computationally modeled the effect of hematocrit variations on the motion of a nearly occluding gas bubble in arterial blood vessels of various sizes. The computational methodology is based on an axisymmetric finite difference immersed boundary numerical method to precisely track the blood-bubble dynamics of the interface. Hematocrit variations are taken to be in the range of 0.2-0.6. The chosen blood vessel sizes correspond to small arteries and small and large arterioles in normal humans. Relevant hydrodynamic interactions between the gas bubble and EC-lined vessel lumen have been characterized and quantified as a function of hematocrit levels. In particular, the variations in shear stress, spatial and temporal shear stress gradients, and the gap between bubble and vascular endothelium surfaces that contribute to EC injury have been computed. The results suggest that in small arteries, the deleterious hydrodynamic effects of the gas embolism on an EC-lined cell wall are significantly amplified as the hematocrit levels increase. However, such pronounced variations with hematocrit levels are not observed in the arterioles.

A novel adipocytokine, nesfatin-1 modulates peripheral arterial contractility and blood pressure in rats

Nesfatin-1 is a novel adipocytokine which exerts not only anorexigenic but also hypertensive roles through acting on hypothalamus melanocortin-3/4 receptors. Although it is logical to hypothesize that nesfatin-1 could also affect the contractile reactivity of peripheral blood vessels, it still remains to be examined. The present study was performed to test the hypothesis. In both endothelium-intact and -denuded mesenteric artery of rats, acute treatment with nesfatin-1 (10nM, 30min pretreatment) had no influence on the noradrenaline- and 5-hydroxytryptamine-induced concentration-dependent contractions. Chronic treatment of mesenteric artery with nesfatin-1 (10nM, 3days) using organ-culture method had also no influence on the agonists-induced contractions. In contrast, nesfatin-1 (10nM, 30min) significantly inhibited the sodium nitroprusside (SNP)-induced relaxations of smooth muscle in mesenteric artery. A membrane permeable cyclic GMP (cGMP) analog, 8-bromo-cGMP-induced relaxations were not affected by nesfatin-1. Consistently, the SNP-induced cGMP production in smooth muscle was impaired by nesfatin-1. Intravenous application of nesfatin-1 to rats not only increased blood pressure but also impaired the SNP-induced decreases in blood pressure. The present study for the first time reveals that nesfatin-1 affects peripheral arterial blood vessel and inhibits the nitric oxide donor-induced smooth muscle relaxations via impairing the cGMP production. The results are the first to demonstrate that nesfatin-1 modulates blood pressure through directly acting on peripheral arterial resistance.

Influence of the aspect ratio on the endovascular treatment of intracranial aneurysms: A computational investigation

Intracranial aneurysm, a localized dilation of arterial blood vessels in the Circle of Willis and its branches, is potentially life threatening, due to massive bleeding in the subarachnoid space upon rupture. In clinical practice, one minimally invasive surgical procedure is the implantation of a metallic stent to cover the aneurysm neck. This flow diverting device can reduce the flow into the aneurysm and enhance the prospect of thrombosis, a condition expected to reduce the risk of growth and rupture. The biomechanical and haemodynamic factors in stented and nonstented situations are studied by computational fluid dynamics. Unlike earlier models with straight or curved parent blood vessels, the aneurysm is now located near an arterial bifurcation. The influence of the aspect (depth to neck) ratio of the aneurysm on the flow dynamics will be emphasized, especially in the post-operation stages. More precisely, the maximum flow velocity, the variations of wall shear stress, the risk of stent migration and volumetric flow rate after endovascular treatment will be studied. Aneurysms with larger aspect ratios (i.e. smaller neck sizes for constant depth) generally pose a greater risk in terms of these flow parameters. These results will assist the applications and design of stents in future neurosurgical therapy. The approach is limited to a nonelastic model, without taking into account of questions like stent expansion and interaction with tissue.

The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease

Cardiovascular disease is the leading cause of death. The disease is due to atherosclerosis which is characterized by lipid and fat accumulation in arterial blood vessel walls. A key causative event is the accumulation of oxidised low density lipoprotein particles within vascular cells, and this is mediated by scavenger receptors. One such molecule is the LOX-1 scavenger receptor that is expressed on endothelial, vascular smooth muscle, and lymphoid cells including macrophages. LOX-1 interaction with OxLDL particles stimulates atherosclerosis. LOX-1 mediates OxLDL endocytosis via a clathrin-independent internalization pathway. Transgenic animal model studies show that LOX-1 plays a significant role in atherosclerotic plaque initiation and progression. Administration of LOX-1 antibodies in cellular and animal models suggest that such intervention inhibits atherosclerosis. Antiatherogenic strategies that target LOX-1 function using gene therapy or small molecule inhibitors would be new ways to address the increasing incidence of vascular disease in many countries.

Effects of Chronic Endothelin ETA Receptor Blockade on Blood Pressure and Vascular Formation of Cyclic Guanosine-3’,5’-monophosphate in Spontaneously Hypertensive Rats

Endothelin (ET) mediates vasoconstriction in intact arterial blood vessels with functional endothelium via stimulation of ET(A) receptors, while ET(B) receptor stimulation leads to vasodilation via nitric oxide (NO) release and formation of cyclic guanosine-3',5'-monophosphate (cGMP). In spontaneously hypertensive rats (SHR) the cGMP-forming NO-receptor guanylyl cyclase (sGC) is downregulated. It is unclear whether ET contributes to the hypertensive phenotype of SHR, and whether this involves the disturbed cGMP signaling. The selective ETA receptor antagonist darusentan (CAS 171714-84-4), given orally via drinking water (10 mg kg(-1) d(-1)) for 12 weeks, significantly lowered systolic blood pressure of SHR as determined by radiotelemetry. Neither impaired endothelium-dependent relaxation to acetylcholine was restored nor sGC expression and activity affected when compared to control SHR. While these findings show a role for ETA receptors in blood pressure regulation in genetically elevated blood pressure, downregulation of sGC expression and cGMP-mediated vasorelaxant response in SHR were shown to be independent of ETA receptors. The findings suggest distinct mechanisms of gene expression affecting ET and cGMP mediated vasomotor functions.

Abstract 9878: Pioglitazone Ameliorates Atherosclerotic Lesions with the Modification of the Balance of Effector and Regulatory T Cells in Apolipoprotein E Deficient Mice

BACKGROUND: Pioglitazone (PIO) affects T cell-mediated immunity through actions of peroxisome proliferator activated receptor γ. Effector and regulatory T cells control the development of atherosclerosis, a chronic inflammatory disease affecting the arterial blood vessels. PURPOSE: The aim of this study was to examine whether PIO ameliorates atherosclerosis by altering the balance of effector and regulatory T cells. METHODS AND RESULTS: To explore the effect of PIO on early and advanced atherosclerosis, apolipoprotein E deficient (ApoE-/-)mice were fed western diet and received PIO (20mg/kg/day) by gastric gavage at 6 or 14 weeks of age, respectively for 8 weeks (each n=12). Data showed that PIO markedly inhibited early fatty streak formation. Although the advanced fibrofatty plaque sizes were not significantly reduced, the numbers of smooth muscle cells within lesions were increased and higher collagen concentrations were produced by PIO. In general, macrophage expression in lesions was decreased by PIO. Additionally, the expression of Foxp3+ cells (regulatory T) was increased in lesions and spleens in mice at all PIO treatment stages, whereas the CD4+interferon-γ+/CD4+interleukin-4+cell ratios were reduced. CONCLUSION: PIO inhibited early atherosclerotic lesion formation and increased the stability of advanced atherosclerotic plaques in ApoE-/- mice, which was associated with altering the balance of effector and regulatory T cells.

Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity

BackgroundCentral to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO).Methodology/Principal FindingsThe hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 µg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (p<0.001), 54% of Low Density Lipoprotein (LDL)-cholesterol (p<0.001) and 34.5% of triglycerides (p<0.001). Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins.ConclusionsGiven the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent and merits further evaluation.

Histological examination of the carotid bifurcation in case of violence against the neck

The carotid body and carotid sinus are localized in the area of the carotid bifurcation and respond to pressure fluctuations in the arterial blood vessel system. In case of irritation or stimulation, nervous impulses can reflexively increase the ventilation or slow down the heart rate and blood pressure, respectively. The external stimulation of the carotid sinus by neck compression with subsequent bradycardia or asystolia, especially in pre-existing heart-disease, is discussed controversially in the literature. Histological examination of the tissue of the carotid bifurcation, particularly with regard to haemorrhage as an indication of tissue trauma, should be carried out in terms of simple and easy feasibility in routine diagnostics. In 20 cases of violence against the neck and additionally 82 cases of a control group without neck trauma and variable causes of death, the carotid bifurcations were examined histologically. Only in one case of violence against the neck haemorrhage was found, which suggested a direct trauma to the tissue of the carotid bifurcation, but evidence of lethal cardiac reflex was not found in any case.

Intracranial aneurysms: from vessel wall pathology to therapeutic approach

An aneurysm is a focal dilatation of an arterial blood vessel. Luminal forces, such as high blood flow, shear stress and turbulence, are implicated in the pathogenesis of intracranial aneurysms, and luminal characteristics, such as sac size and morphology, are usually essential to the clinical decision-making process. Despite frequent clinical emphasis on the vessel lumen, however, the pathology underlying the formation, growth and rupture of an aneurysm mainly resides in the vessel wall. Research on the morphology and histopathology of the vessel wall reveals that intracranial aneurysms do not constitute a single disease, but are a shared manifestation of a wide range of diseases, each of which has a unique natural history and optimum therapy. This Review classifies intracranial aneurysms by vessel wall pathology, and demonstrates that understanding the morphology and pathology of this structure is important in determining the therapeutic approach. The article concludes that aneurysms represent a symptom of an underlying vascular disease rather than constituting a disease on their own.