Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice.

Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional allele (ßA-Akt1WT/flx) was viable. Fewer than expected numbers of ßA-Akt1WT/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe, but generally ßA-Akt1WT/flx embryos had fewer visible blood vessels and more hemorrhages than their wild-type littermates, which was suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared with wild-type skin. By E15.5, wild-type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in ßA-Akt1WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in ßA-Akt1WT/flx skin compared with that of wild type. Restricting expression of Akt1E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the ßA-Akt1WT/flx phenotype. We conclude that ubiquitous expression of Akt1E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.

Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations.

Oncogenic RAS variants lead to constitutive overactivation and increased signal transduction into downstream pathways. They are found as somatic driver events in various types of human cancer. In a somatic mosaic status, the same RAS variants have been associated with a wide spectrum of focal or segmental tissue dysplasia and overgrowth including various types of congenital nevi, vascular malformations, and other changes (mosaic RASopathies). We present a 3-year-old male patient with segmental overgrowth of the subcutaneous fatty tissue of the right lower extremity with colocalized arteriovenous and capillary malformations and dysplastic draining veins in combination with talipes equinovarus of the right foot. In tissue biopsies of the affected extremity, we identified a mosaic KRAS variant, c.35G>A (p.Gly12Asp), while this variant was absent in the DNA extracted from a biopsy of the normal extremity. This report provides further evidence for the wide clinical and phenotypic variability associated with mosaic KRAS variants. The described pattern confirms that the combination of segmental overgrowth and vascular anomalies in the form of arteriovenous and capillary malformations is a possible manifestation of a mosaic RASopathy. The accurate genetic diagnosis is crucial for molecular-targeted therapy, which might be a future therapeutic target for mosaic RASopathies.

Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID-19 patients.

As a respiratory viral infection caused by a novel coronavirus, COVID-19 became rapidly pandemic within a few months. Despite the wide range of manifestations and organ involvement in COVID-19 patients, the exact pathogenesis of severe and fatal types of COVID-19 and causes involved with the individual base of the disease is not yet understood. Several studies have reported clinical, laboratory, and histopathological data in favor of vascular injury in multiple organs of critically ill patients with COVID-19 as a result of hyperactive immune response, inflammation, and cytokine storm. Also, both clinical and histopathological evidence points to such vascular involvements in the skin. Given the ease of clinical examinations and skin biopsy and the lower risks of transmission of COVID-19 to healthcare workers, the present review article was conducted to investigate the vascular skin manifestations of COVID-19 patients clinically and/or histopathologically as helpful clues for better understanding the pathogenesis and predicting the prognosis of the disease, especially in severe cases.

Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection.

Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation-cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control-could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement.

Successful treatment of lymphedema in a vasculopath and neuropathic patient.

This is a case report of a 68-year-old male with stage III right lower extremity lymphedema following right inguinal lymph node dissection and adjuvant chemoradiotherapy for Hodgkin's lymphoma. He developed peripheral neuropathy and radiation-induced right femoral artery thrombosis, treated with saphenous vein graft. He underwent three vascularized lymph node transfers (VLNTs) to the upper medial thigh, posterior calf, and ankle with placement of nanofibrillar collagen scaffolds. Three months after surgery, he had volume reduction, less neuropathic pain, and improved ambulation.

Histopathological and proteomic analyses identify integrin-ß1 as a potential mediator of phlebosclerosis in uremic patients.

BACKGROUND: Patients with uremia have an excessive mortality from cardiovascular disease (CVD). Arterial remodeling is mainly responsible for uremia-induced CVD and has been well studied, yet venous remodeling is poorly understood. Here we investigate the histopathology and proteomic profiles of venous remodeling in uremic patients. METHODS: Forearm cephalic veins were isolated from nine uremic patients during surgeries for arteriovenous fistula, and from nine healthy controls when applying surgical debridement. Hematoxylin-eosin, Masson's trichrome, von Kossa, and immunohistochemistry (IHC) against proliferating cell nuclear antigen were stained for histopathology. Isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis was executed to explore the proteome of the veins. The core regulatory protein was validated by western blot, IHC, and immunofluorescence. RESULTS: Phlebosclerosis, characterized by intimal rarefaction and medial thickening with disordered proliferation of vascular smooth muscle cells (VSMCs), was the prominent pathological manifestation of peripheral veins in uremic patients, while inflammatory cell infiltration, atherosclerosis or calcification were not obviously detected. iTRAQ analysis showed that 350 proteins were significantly changed in phlebosclerosis of uremic patients compared with healthy controls, of which integrin-ß1 (ITGß1) exhibited the strongest regulatory ability by intermolecular interaction network analysis. The enhanced ITGß1 expression was mainly co-expressed with the disordered proliferation of VSMCs while a little with vascular endothelial cells in the forearm cephalic veins of uremic patients. CONCLUSIONS: Phlebosclerosis is the prominent pathological manifestation in peripheral veins of uremic patients. This pathological alteration mainly attributes to the disordered proliferation of VSMCs, which is potentially mediated by ITGß1.

Is 64-Row Multi-Detector Computed Tomography Angiography Equal to Digital Subtraction Angiography in Treatment Planning in Critical Limb Ischemia?

BACKGROUND: Critical limb ischemia (CLI) represents the end stage of peripheral arterial disease (PAD). It is defined as a chronic ischemic rest pain, ulcers or gangrene, attributable to proven arterial occlusive disease. Intra-arterial digital subtraction angiography (IA DSA) still represents the gold standard for the evaluation of steno-occlusive lesions, but it has greatly been replaced with non-invasive multi-detector computed tomography angiography (MDCTA). The purpose of this prospective study was to compare diagnostic performance of MDCTA versus DSA in treatment planning in patients with CLI according to TransAtlantic Inter-Society Consensus Document on Management of Peripheral Arterial disease (TASC II). SUBJECTS AND METHODS: The study was designed as prospective; it was conducted from March 2014 to August 2016, and included 60 patients with symptoms of CLI, Fontaine stage III and IV. MDCTA of the peripheral arteries was performed first, followed by DSA. The lesions of aorto-iliac, femoro-popliteal and infra-popliteal regions were classified according to the TASC II guidelines, and inter-modality agreement between MDCTA and DSA was determined by using Kendall's tau-b statistics. RESULTS: Inter-modality agreement was statistically significant in all three vascular beds, with excellent agreement >0.81 in aortoiliac and femoropopliteal regions, and a very good agreement >0.61 in infrapopliteal region. Treatment recommendations based on MDCTA findings and DSA findings were identical in 54 (90%) patients. In one patient (1.7%), CTA was not interpretable. In five patients (8.3%), CTA findings disagreed with DSA findings in regard to the preferable treatment option. CONCLUSION: 64-row MDCT angiography is highly competitive to DSA in evaluation of steno-occlusive disease and treatment planning in patients with critical limb ischemia.

Chronic atorvastatin and exercise can partially reverse established skeletal muscle microvasculopathy in metabolic syndrome.

It has long been known that chronic metabolic disease is associated with a parallel increase in the risk for developing peripheral vascular disease. Although more clinically relevant, our understanding about reversing established vasculopathy is limited compared with our understanding of the mechanisms and development of impaired vascular structure/function under these conditions. Using the 13-wk-old obese Zucker rat (OZR) model of metabolic syndrome, where microvascular dysfunction is sufficiently established to contribute to impaired skeletal muscle function, we imposed a 7-wk intervention of chronic atorvastatin treatment, chronic treadmill exercise, or both. By 20 wk of age, untreated OZRs manifested a diverse vasculopathy that was a central contributor to poor muscle performance, perfusion, and impaired O2 exchange. Atorvastatin or exercise, with the combination being most effective, improved skeletal muscle vascular metabolite profiles (i.e., nitric oxide, PGI2, and thromboxane A2 bioavailability), reactivity, and perfusion distribution at both individual bifurcations and within the entire microvascular network versus responses in untreated OZRs. However, improvements to microvascular structure (i.e., wall mechanics and microvascular density) were less robust. The combination of the above improvements to vascular function with interventions resulted in an improved muscle performance and O2 transport and exchange versus untreated OZRs, especially at moderate metabolic rates (3-Hz twitch contraction). These results suggest that specific interventions can improve specific indexes of function from established vasculopathy, but either this process was incomplete after 7-wk duration or measures of vascular structure are either resistant to reversal or require better-targeted interventions. NEW & NOTEWORTHY We used atorvastatin and/or chronic exercise to reverse established microvasculopathy in skeletal muscle of rats with metabolic syndrome. With established vasculopathy, atorvastatin and exercise had moderate abilities to reverse dysfunction, and the combined application of both was more effective at restoring function. However, increased vascular wall stiffness and reduced microvessel density were more resistant to reversal. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/reversal-of-microvascular-dysfunction/ .

Macular capillary recovery in systemic lupus erythematosus complicated by Kikuchi-Fujimoto disease.

PURPOSE: Few case reports have described vaso-occlusive retinopathy in systemic lupus erythematosus (SLE) using optical coherence tomography (OCT) angiography. Here we report the clinical features of a patient with SLE, complicated by Kikuchi-Fujimoto disease, who developed vaso-occlusive retinopathy. We then describe the subsequent recovery of the macular capillaries as assessed by OCT angiography. CASE: A 16-year-old male was referred to us with fever, a 1-month history of violaceous red papules and erythematous plaques on his face and a painful nodule in his right neck. We diagnosed him with SLE complicated by Kikuchi-Fujimoto disease through physiological assessment and histology from his neck lymph node and chin skin. Systemic steroids were prescribed as treatment. After remission, his fever and cervical lymph node swelling with pain recurred and he developed blurred inferior vision in his left eye. His best-corrected visual acuities were 1.0 and 0.1 in the right and left eyes, respectively. Extensive cotton wool spots were observed in the right fundus, and retinal capillary occlusions were detected by OCT angiography of the left eye. We diagnosed this case as vaso-occlusive retinopathy with SLE and increased immunosuppressive treatment together with anticoagulation therapy. Macular capillaries, observed by OCT angiography, gradually recovered function following assessment at 7 and 16 months post-onset of the vaso-occlusive retinopathy. CONCLUSIONS: We reported a 1½-year course of vaso-occlusive retinopathy in a patient with SLE complicated by Kikuchi-Fujimoto disease. Occlusion of the retinal vasculature and the subsequent recovery of circulation are clearly observed by OCT angiography.

Handy Hints About Raynaud's Phenomenon in Children: A Critical Review.

Raynaud's phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited episodes of skin pallor, cyanosis, and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes and can occur in any age group. Hands, feet, nose, ears, and nipples can be affected. The diagnosis is made clinically, assessing varying degrees of ischemia in the involved areas of skin, but this transient ischemia may also herald the onset of connective tissue disease. Investigation is recommended when RP starts in childhood to exclude an underlying autoimmune condition and close follow-up for its development. Management of RP in children includes conservative and pharmacologic treatments.

[Effect of actovegin and solcoseryl on microcirculation in experimental critical lower limb ischaemia]. / Vliianie aktovegina i solkoserila na mikrotsirkuliatsiiu pri kriticheskoi ishemii nizhnikh konechnostei v éksperimente.

The authors examined the effect of actovegin and solcoseryl on microcirculation parameters in treatment of experimental critical lower limb ischaemia. The study included a total of 130 male Wistar albino rats divided into four groups: intact, control, first and second study groups. The intact group consisted of 10 animals used for assessment of the normal indices of microcirculation, with the remaining three groups comprising 40 rats each. All animals, except the intact ones, were subjected to modelled critical ischaemia of a hind limb. The control group animals received no treatment, with the rats of the first and second study groups given intraperitoneal actovegin and solcoseryl, respectively, at a dose of 50 µg/kg first injected 3 hours after the operation and then once daily for five days. The level of microcirculation in the murine crural muscles was assessed by means of laser Doppler flowmetry on postoperative days 5, 10, 21 and 28. At the same time intervals, we performed histological examination of the ischaemized muscles, determining the level of microcirculation, the level of arteriovenular shunting, the area of necrosis and capillary network density. It was determined that actovegin and solcoseryl exerted a positive effect on formation of new capillaries in the ischaemized muscles, increasing density of the capillary network, decreasing arteriovenular shunting, increasing the level of microcirculation, decreasing the specific area of muscular tissue necrosis. The obtained findings showed advantages of actovegin over solcoseryl by the dynamics of the parameters of microcirculation, arteriovenular shunting, and capillary network density.

Noncontrast-enhanced peripheral venography using velocity-selective magnetization preparation and transient balanced SSFP.

PURPOSE: To develop a three-dimensional (3D) noncontrast-enhanced (NCE) peripheral magnetic resonance venography (MRV) method and demonstrate its feasibility in vivo. METHODS: The proposed MRV pulse sequence consisted of a velocity-selective (VS) inversion preparation module, inversion delay time (TI), fat inversion pulse, and 3D balanced steady-state free precession (bSSFP) dummy excitations and readout. The VS preparation module inverted arterial blood, which recovered close to zero magnetization during TI. The TI and the number of dummy excitations (Nnum ) were numerically optimized for maximizing vein-to-background contrast and tested in a healthy subject. The proposed MRV of the entire peripheral system, using four-station acquisition, was performed in six healthy subjects and three peripheral artery patients. RESULTS: The numerical optimization yielded TI = 350 ms and Ndum = 40, which was supported by the largest vein contrast among the parameters chosen around the optima on in vivo venograms. Four-station peripheral MRV using the optimized parameters well visualized all major deep veins with high vein-to-background contrast. The relative vein contrast ratios were 0.80 ± 0.08, 0.75 ± 0.07, and 0.84 ± 0.06 against the arteries, muscle, and fat, respectively. CONCLUSION: The proposed NCE MRV using VS preparation and transient bSSFP can generate high-contrast peripheral venograms directly with a single acquisition.

Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation.

Diabetes is strongly associated with systemic inflammation and oxidative stress, but its effect on pulmonary vascular disease and lung function has often been disregarded. Several studies identified restrictive lung disease and fibrotic changes in diabetic patients and in animal models of diabetes. While microvascular dysfunction is a well-known complication of diabetes, the mechanisms leading to diabetes-induced lung injury have largely been disregarded. We described the potential involvement of diabetes-induced platelet-endothelial interactions in perpetuating vascular inflammation and oxidative injury leading to fibrotic changes in the lung. Changes in nitric oxide synthase (NOS) activation and decreased NO bioavailability in the diabetic lung increase platelet activation and vascular injury and may account for platelet hyperreactivity reported in diabetic patients. Additionally, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been reported to mediate pancreatic islet damage, and is implicated in the onset of diabetes, inflammation and vascular injury. Many growth factors and diabetes-induced agonists act via the JAK/STAT pathway. Other studies reported the contribution of the JAK/STAT pathway to the regulation of the pulmonary fibrotic process but the role of this pathway in the development of diabetic lung fibrosis has not been considered. These observations may open new therapeutic perspectives for modulating multiple pathways to mitigate diabetes onset or its pulmonary consequences.

Differential Diagnosis of Chronic Total Occlusive and Subtotal Occlusive Disease of the Lower Extremity Arteries Using Reverse Attenuation Gradient Sign on CT Angiography.

OBJECTIVE: The purpose of this study is to evaluate the diagnostic usefulness of the reverse attenuation gradient sign in occlusive lower extremity arterial disease through CT angiography (CTA). MATERIALS AND METHODS: This study sample enrolled 45 men and eight women in the chronic total occlusion group and 30 men and seven women in the subtotal occlusion group. Luminal CT attenuation (in Hounsfield units) was measured at three points from the end of the occlusion site to the first collateral vessel's insertion point. We also used Hounsfield units to measure the CT attenuation of the opposite side artery at the same level in a similar manner. We compared each value using the Mann-Whitney U test. RESULTS: The absolute value of the mean differences in the Hounsfield units among the proximal, middle, and distal portion of chronic total occlusions were higher than those of subtotal occlusions, and this result was statistically significant (p < 0.001). The mean ratios of the Hounsfield units (Hounsfield units of the stenosed lumen divided by Hounsfield units of the opposite normal lumen) of the proximal portion of chronic total occlusions were statistically significantly lower than those of subtotal occlusions. CONCLUSION: The reverse attenuation gradient sign can be applied to the lower extremity arteries and can be helpful for differential diagnosis of chronic total occlusions from subtotal occlusions using CTA.

The relationship between nailfold capillaroscopic assessment and telangiectasia score with severity of peripheral vascular involvement in systemic sclerosis.

OBJECTIVES: To determine the association of nailfold video-capillaroscopy (NVC) findings and telangiectasia score with digital ulcer (DU) history and severity of peripheral vascular involvement (PVI) in systemic sclerosis (SSc). METHODS: Fifty-nine SSc patients fulfilling Leroy & Medsger criteria were evaluated including telangiectasia score, disease activity and severity scores. NVC was performed according to qualitative (early, active and late patterns) and semi-quantitative assessments. RESULTS: When DU+ and DU- groups were compared; the mean score of capillary number (CN) was 2.0±0.5 vs. 1.4±0.7 (p<0.001), irregularly enlarged capillaries (IEC) was 1.8±0.6 vs. 1.4±0.7 (p<0.05), microangiopathy evolution score (MES) was 2.5±1.5 vs. 1.8±1.0 (p<0.05) and 'early' pattern was significantly less frequent in DU+ patients (1 vs. 9, p=0.016). The frequency of severe-PVI (Medsger severity score of 2-4) was 22% in females (12/54) and 80% in males (4/5). When severe and non-severe groups were compared; the mean score of CN was 2.1±0.4 vs. 1.5±0.7 (p<0.001), MES was 2.8±1.6 vs. 1.8±1.1 (p<0.05) and 'early' pattern was significantly less frequent in patients with severe PVI (0 vs. 9, p=0.049). The mean values of telangiectasia score were similar between groups. CONCLUSIONS: DU history and severe PVI in SSc were associated with capillary loss and microangiopathy. 'Early' NVC pattern was very rare in patients with DU history and was not found in severe PVI. Severe PVI in males was more frequent than females. Telangiectasia scores were not found to be related to PVI. NVC may be a helpful method in the assessment of SSc patients for PVI prognosis, warranting prospective studies.

[Cystic degeneration of the popliteal artery: Report of one case]. / Degeneración quística de la arteria poplítea: Presentación de caso clínico.

Cystic degeneration of the popliteal artery is an uncommon cause of intermittent claudication. We report a 52 years old male consulting for intermittent claudication referred to the calf. The angiography showed a 93% stenosis in segment of 45 mm length of the left popliteal artery with a smooth surface, suggesting an extrinsic compression. A CT angiography of the lower limb suggested the presence of a cystic degeneration. The patient was operated and the middle third of the popliteal artery was excised. The pathological study of the surgical piece was informed as artery media cystic degeneration.

[The Evidence for the Treatment of Polypoidal Choroidal Vasculopathy].

The optimal treatment of polypoidal choroidal vasculopathy (PCV) is still undetermined. Photodynamic therapy (PDT) is effective for PCV but the Treatment effect declines after one year. While some reports show the efficacy of anti-vascular endothelial growth factor (VEGF) therapy for PCV, other reports show treatment-refractory cases. In this article, the author reviews the results of our multicenter randomized trial, conducted to compare the efficacy of PDT and ranibizumab in PCV patients. The results showed that ranibizumab is more effective in visual gain in two-year follow up. Central retinal thickness improved with both treatments and there was no difference between them. Our results provide evidence that ranibizumab is superior to PDT monotherapy for treatment of PCV in terms of visual acuity.

Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?

OBJECTIVE: Urokinase-type plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodelling and angiogenesis. The cleavage/inactivation of uPAR is a crucial step in fibroblast-to-myofibroblast transition and has been implicated in systemic sclerosis (SSc) microvasculopathy. In the present study, we investigated whether uPAR gene inactivation in mice could result in tissue fibrosis and peripheral microvasculopathy resembling human SSc. METHODS: The expression of the native full-length form of uPAR in human skin biopsies was determined by immunohistochemistry. Skin and lung sections from uPAR-deficient (uPAR(-/-)) and wild-type (uPAR(+/+)) mice at 12 and 24 weeks of age were stained with haematoxylin-eosin, Masson's trichrome and Picrosirius red. Dermal thickness and hydroxyproline content in skin and lungs were quantified. Dermal myofibroblast and microvessel counts were determined by immunohistochemistry for α-smooth muscle actin and CD31, respectively. Endothelial cell apoptosis was assessed by TUNEL/CD31 immunofluorescence assay. RESULTS: Full-length uPAR expression was significantly downregulated in SSc dermis, especially in fibroblasts and endothelial cells. Dermal thickness, collagen content and myofibroblast counts were significantly greater in uPAR(-/-) than in uPAR(+/+) mice. In uPAR(-/-) mice, dermal fibrosis was paralleled by endothelial cell apoptosis and severe loss of microvessels. Lungs from uPAR(-/-) mice displayed non-specific interstitial pneumonia-like pathological features, both with inflammation and collagen deposition. Pulmonary pathology worsened significantly from 12 to 24 weeks, as shown by a significant increase in alveolar septal width and collagen content. CONCLUSIONS: uPAR(-/-) mice are a new animal model closely mimicking the histopathological features of SSc. This model warrants future studies.