Posttraumatic arteriovenous fistula of the lower extremity and the pathological characteristic-case series and literature review.

The clinical presentation, treatment history, and outcomes of two patients with posttraumatic arteriovenous fistula (PTAVF) were analyzed and compared with the pathological tissues of patients with hemodialysis arteriovenous fistula (HAVF). A search of the biomedical literature database (PubMed), using the keywords " lower extremity" and "PTAVF," was conducted to obtain results and review the data. Postoperative histological analysis of patients with PTAVF showed differences from that of HAVF. The literature screening and analysis revealed that PTAVF is a chronic progressive process, with 70% of patients diagnosed after 3 months. The choice of treatment revealed that 20% of patients had severe complications and all were treated endovascularly. Due to the abnormal fistula of PTAVF and its specific histopathological features, the disease is not self-limiting. It is unwise to wait for PTAVF to cause "failure." We recommend early and timely cure of this disease by surgery to avoid serious complications.

PKCδ regulates the vascular biology in diabetic atherosclerosis.

Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as a common vascular complication mechanism in diabetes. The diacylglycerol (DAG)-protein kinase C (PKC) pathway plays an important role in atherosclerosis. PKCs can be divided into three subgroups: conventional PKCs (cPKCs), novel PKCs (nPKCs), and atypical PKCs (aPKCs). The aim of this review is to provide a comprehensive overview of the role of the PKCδ pathway, an isoform of nPKC, in regulating the function of endothelial cells, vascular smooth muscle cells, and macrophages in diabetic atherosclerosis. In addition, potential therapeutic targets regarding the PKCδ pathway are summarized. Video Abstract.

The Role of TGF-ß Signaling in Saphenous Vein Graft Failure after Peripheral Arterial Disease Bypass Surgery.

Saphenous vein bypass grafting is an effective technique used to treat peripheral arterial disease (PAD). However, restenosis is the major clinical challenge for the graft vessel among people with PAD postoperation. We hypothesize that there is a common culprit behind arterial occlusion and graft restenosis. To investigate this hypothesis, we found TGF-ß, a gene specifically upregulated in PAD arteries, by bioinformatics analysis. TGF-ß has a wide range of biological activities and plays an important role in vascular remodeling. We discuss the molecular pathway of TGF-ß and elucidate its mechanism in vascular remodeling and intimal hyperplasia, including EMT, extracellular matrix deposition, and fibrosis, which are the important pathways contributing to stenosis. Additionally, we present a case report of a patient with graft restenosis linked to the TGF-ß pathway. Finally, we discuss the potential applications of targeting the TGF-ß pathway in the clinic to improve the long-term patency of vein grafts.

Identification and Validation of PTGS2 Gene as an Oxidative Stress-Related Biomarker for Arteriovenous Fistula Failure.

(1) Background: Arteriovenous fistulas (AVFs) are the preferred site for hemodialysis. Unfortunately, approximately 60% of patients suffer from AVF failure within one year. Oxidative stress plays an important role in the occurrence and development of AVF. However, the underlying mechanisms remain unclear. Therefore, specific oxidative stress-related biomarkers are urgently needed for the diagnosis and treatment of AVF failure. (2) Methods: Bioinformatics analysis was carried out on dataset GSE119296 to screen for PTGS2 as a candidate gene related to oxidative stress and to verify the expression level and diagnostic efficacy of PTGS2 in clinical patients. The effects of NS398, a PTGS2 inhibitor, on hemodynamics, smooth muscle cell proliferation, migration, and oxidative stress were evaluated in a mouse AVF model. (3) Results: Based on 83 oxidative stress-related differentially expressed genes, we identified the important pathways related to oxidative stress. PTGS2 may have diagnostic and therapeutic efficacy for AVF failure. We further confirmed this finding using clinical specimens and validation datasets. The animal experiments illustrated that NS398 administration could reduce neointimal area (average decrease: 49%) and improve peak velocity (average increase: 53%). (4) Conclusions: Our study identified PTGS2 as an important oxidative stress-related biomarker for AVF failure. Targeting PTGS2 reduced oxidative stress and improved hemodynamics in an AVF mouse model.

Cervical vagal nerve schwannoma induced arrhythmia: a rare case report and literature review.

BACKGROUND: Schwannomas are benign tumors deriving from the sheath of cranial and peripheral nerves. The vagus nerve is comprised of a complex neuro-endocrine-immune network that maintains homeostasis, most tracts of it play a role in parasympathetic activity. We present an example of a rare cervical vagal schwannoma case accompanied by arrhythmia. CASE PRESENTATION: A 35-year-old female patient with a left cervical vagus schwannoma and ventricular arrhythmia underwent schwannoma resection in the operating room. The patient's suppressed heart rate increased after tumor removal, and the cardiac rhythm returned to normal postoperatively. Pathological examination demonstrated the diagnosis of schwannoma. CONCLUSIONS: This case explains the link between the vagus nerve and the cardiovascular system, proving that a damaged cervical vagus nerve can inhibit the heart rate and lead to arrhythmias, and eventually requiring surgical intervention.

CXCR4+ Sorted Adipose-Derived Stem Cells Enhance Their Functional Benefits and Improve Cardiac Function after Myocardial Infarction.

Objective: The homing of adipose-derived stem cells (ASCs) to infarcted myocardium, which is important for improved cardiac function, has been investigated previously, but with poor efficiency. Substantial improvements in engraftments are required to optimize ASC treatment. Stromal derived factor-1α (SDF-1α) is upregulated early after MI, and its endogenous receptor, chemokine receptor 4 (CXCR4), is pivotal in stem cell survival, migration, and engraftment. We examined whether CXCR4+ ASCs enhance their efficacy of migration and engraftment posttransplantation and improve heart function following myocardial infarction (MI). Methods and Results: CXCR4+ ASC subpopulations were sorted by fluorescence-activated cell sorting. CXCR4+ sorted ASCs exhibited the stronger cell viability, the faster proliferation rate, and the better migration capability in comparison with unfractionated ASCs. CXCR4+ sorted ASCs secreted a higher level of angiogenic growth factors including VEGF, HGF, and IGF-1 relative to unfractionated ASCs. Fewer apoptotic cells under oxygen-glucose deprivation were detected in CXCR4+ sorted ASCs than in unfractionated ASCs. Osteogenic and angiogenic differentiation were more pronounced in CXCR4+ sorted ASCs than in unfractionated ASCs. At 3 days after acute MI, rats were randomly allocated to receive intramyocardial injection of cell culture medium, CXCR4+ sorted ASCs, and unfractionated ASCs. Left ventricular function was assessed echocardiographically 4 weeks thereafter. Explanted hearts were then processed for the immunofluorescence detection of survived cells, quantification of angiogenesis, and cell engraftment. CXCR4+ sorted ASCs more obviously engrafted into infarcted myocardium, more markedly inhibited collagen remodeling, and more effectively improved heart function and promoted capillary formation than did unfractionated ASCs. Conclusion: CXCR4+ sorted ASCs are superior to unfractionated ASCs due to better viability, faster proliferation, more cytokine secretion, and stronger migration. CXCR4+ sorted ASCs provide better curative benefits on MI than do unfractionated ASCs and can be efficiently harvested and purified from adipose tissue, they may serve as a promising candidate for MI.

Oxidative stress: An essential factor in the process of arteriovenous fistula failure.

For more than half a century, arteriovenous fistula (AVFs) has been recognized as a lifeline for patients requiring hemodialysis (HD). With its higher long-term patency rate and lower probability of complications, AVF is strongly recommended by guidelines in different areas as the first choice for vascular access for HD patients, and its proportion of application is gradually increasing. Despite technological improvements and advances in the standards of postoperative care, many deficiencies are still encountered in the use of AVF related to its high incidence of failure due to unsuccessful maturation to adequately support HD and the development of neointimal hyperplasia (NIH), which narrows the AVF lumen. AVF failure is linked to the activation and migration of vascular cells and the remodeling of the extracellular matrix, where complex interactions between cytokines, adhesion molecules, and inflammatory mediators lead to poor adaptive remodeling. Oxidative stress also plays a vital role in AVF failure, and a growing amount of data suggest a link between AVF failure and oxidative stress. In this review, we summarize the present understanding of the pathophysiology of AVF failure. Furthermore, we focus on the relation between oxidative stress and AVF dysfunction. Finally, we discuss potential therapies for addressing AVF failure based on targeting oxidative stress.

Ferroptosis in Cardiovascular Diseases: Current Status, Challenges, and Future Perspectives.

Cardiovascular diseases (CVDs) are still a major cause of global mortality and disability, seriously affecting people's lives. Due to the severity and complexity of these diseases, it is important to find new regulatory mechanisms to treat CVDs. Ferroptosis is a new kind of regulatory cell death currently being investigated. Increasing evidence showed that ferroptosis plays an important role in CVDs, such as in ischemia/reperfusion injury, heart failure, cardiomyopathy, and atherosclerosis. Protecting against CVDs by targeting ferroptosis is a promising approach; therefore, in this review, we summarized the latest regulatory mechanism of ferroptosis and the current studies related to each CVD, followed by critical perspectives on the ferroptotic treatment of CVDs and the future direction of this intriguing biology.

Targeting TNF-α for COVID-19: Recent Advanced and Controversies.

Recent advances in the pathophysiologic understanding of coronavirus disease 2019 (COVID-19) suggests that cytokine release syndrome (CRS) has an association with the severity of disease, which is characterized by increased tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-2, IL-7, and IL-10. Hence, managing CRS has been recommended for rescuing severe COVID-19 patients. TNF-α, one of the pro-inflammatory cytokines commonly upregulated in acute lung injury, triggers CRS and facilitates SARS-CoV-2 interaction with angiotensin-converting enzyme 2 (ACE2). TNF-α inhibitors, therefore, may serve as an effective therapeutic strategy for attenuating disease progression in severe SARS-CoV-2 infection. Below, we review the possibilities and challenges of targeting the TNF-α pathway in COVID-19 treatment.

Endovascular therapy for distal hilar renal artery aneurysm: a case report and literature review.

Renal artery aneurysm (RAA), a type of visceral aneurysm with atypical symptoms, is difficult to detect and is usually discovered incidentally by imaging examination. Hilar RAA (HRAA) represents a relatively rare subgroup of RAA that is located in the distal part of the renal artery, close to the renal parenchyma. We reported a 55-year-old woman with an HRAA measuring 19 mm × 20 mm × 20 mm. She underwent endovascular therapy with bare-metal stent implantation with nested coil embolization. She was discharged without complications. The uniqueness of this case is the aneurysm location, which was at the distal right renal artery, making it difficult to preserve the blood supply to the right kidney. The novelty of the minimally invasive technique was that this endovascular treatment not only eliminated the aneurysm, but also preserved the blood supply to the ipsilateral kidney. Endovascular therapy is effective in the management of HRAA.

Sex Differences in Arteriovenous Fistula Failure: Insights from Bioinformatics Analysis.

(1) Background: Arteriovenous fistulas (AVFs) are the preferred access for hemodialysis. Unfortunately, about 60% of patients, especially female patients, fail to receive normal dialysis within one year after surgery because of AVF failure. However, the underlying mechanisms caused by sex differences in AVF failure remain unclear. (2) Methods: We performed analysis of DEGs and functional analysis with the dataset GSE119296 to reveal the biology underlying AVF failure. Immune responses were calculated using CIBERSORT. A protein-protein interaction network and hub gene were constructed using STRING and stepwise identification of potential drugs was performed online. (3) Results: Functional analysis showed that extracellular matrix reprogramming and PI3K-AKT pathway enrichment were significant in both male and female patients. COL1A1 was the hub gene in male patients, whereas CDK1 was the hub gene in female patients. Immune responses including γδ-T cells and mast cells are activated in female patients while no significant differences were noted in the male group. (4) Conclusions: In this study, we used a series of mature and recognized bioinformatic strategies to determine the following items: (1) Reveal the pathogenesis of AVF failure through HUB genes and signaling pathways between the different sexes. (2) Determine the relationship between sex differences in AVF failure and immune abnormalities. (3) Search for relevant sex-specific drugs targeting AVF failure.

Identification of novel therapeutic targets for contrast induced acute kidney injury (CI-AKI): alpha blockers as a therapeutic strategy for CI-AKI.

Iodinated contrast is used for imaging and invasive procedures and it can cause contrast induced acute kidney injury (CI-AKI), which is the third leading hospital-acquired health problem. The purpose of the present study was to determine the effect of α-adrenergic receptor-1b (Adra1b) inhibition by using terazosin on change in kidney function, gene, and protein expression in C57BL/6J male mice, 6-8 weeks with chronic kidney disease (CKD). CKD was induced by surgical nephrectomy. Twenty eight days later, 100-µL of iodinated contrast (CI group) or saline (S group) was given via the carotid artery. Whole-transcriptome RNA-sequencing (RNA-Seq) analysis of the kidneys was performed at day 2. Mice received either 50-µL of saline ip or terazosin (2 mg/kg) in 50-µL of saline ip 1 hour before contrast administration which was continued every 12 hours until the animals were euthanized 2 and 7 days later. The kidneys were removed for gene expression, immunohistochemical analysis, and blood serum analyzed for kidney function. Differential gene expression analysis identified 21 upregulated and 436 downregulated genes (fold change >2; P < 0.05) that were common to all sample (n = 3 for both contrast and saline). We identified Adra1b using bioinformatic analysis. Mice treated with terazosin had a significant decrease in serum creatinine, urinary Kim-1 levels, HIF-1α, apoptosis, and downstream Adrab1 genes including Ece1, Edn1, pMAPK14 with increased cell proliferation. Contrast exposure upregulated Adra1b gene expression in HK-2 cells. Inhibition of Adra1b with terazosin abrogated Ece1, Edn1, and contrast-induced Fsp-1, Mmp-2, Mmp-9 expression, and caspase-3/7 activity in HK-2 cells.

1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas.

BACKGROUND: Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model. METHODS: Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF. RESULTS: Encapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFß1, and apoptotic pathways. CONCLUSIONS: Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model.

Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D3, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C-C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-µL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson's trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.

Deep Venous Thrombosis in COVID-19 Patients: A Cohort Analysis.

Deep venous thrombosis (DVT) is a severe complication of coronavirus disease 2019 (COVID-19). The purpose of this study was to study the prevalence, risk factors, anticoagulant therapy and sex differences of DVT in patients with COVID-19. The enrolled 121 hospitalized non-ventilator patients were confirmed positive for COVID-19. All suspected patients received color Doppler ultrasound (US) to screen for DVT in both lower extremities. Multivariate logistic regression was performed to identify risk factors related to DVT in COVID-19 patients. DVT was found in 48% of the asymptomatic COVID-19 patients with an increased PADUA or Caprini index using US scanning. The multivariate logistic regression determined that age (OR, 1.05; p = .0306), C-reactive protein (CRP) (OR, 1.02; p = .0040), and baseline D-dimer (OR, 1.42; p = .0010) were risk factors among COVID-19 patients. Although the most common DVT location was infrapopliteal (classes I and II), higher mortality in DVT-COVID-19 patients was confirmed. DVT-COVID-19 patients presented significant increases in CRP, neutrophil count, and D-dimer throughout the whole inpatient period compared to non-DVT-COVID-19 patients. Although anticoagulation therapy accelerated the recovery of lymphocytopenia in DVT patients, men DVT-COVID-19 patients with anticoagulant therapy showed significant higher CRP and neutrophil count vs. lymphocyte count (N/L) ratio, but showed lower lymphocyte counts compared to women DVT-COVID-19 patients. DVT is common in COVID-19 patients with high-risk factors, especially for older age and higher CRP and baseline D-dimer populations. It is important to consider sex differences in anticoagulant therapy among DVT-COVID-19 patients.

Periadventitial Delivery of Simvastatin-Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula.

Background Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end-stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP-SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease. Methods and Results Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 µL of PBS or 20 µL of PBS with 16.6 mg/mL of either MP or MP-SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase-polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor-A (Vegf-A), matrix metalloproteinase-9 (Mmp-9), transforming growth factor beta 1 (Tgf-ß1), and monocyte chemoattractant protein-1 (Mcp-1) were significantly decreased in MP-SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP-SV treated outflow veins. MP-SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of Vegf-A and Mmp-9. Conclusions In experimental arteriovenous fistulas, periadventitial delivery of MP-SV decreased gene expression of Vegf-A, Mmp-9, Tgf-ß1 and Mcp-1, VNH/VS, inflammation, and fibrosis.

Experimental murine arteriovenous fistula model to study restenosis after transluminal angioplasty.

Percutaneous transluminal angioplasty (PTA) is a very common interventional treatment for treating stenosis in arteriovenous fistula (AVF) used for hemodialysis vascular access. Restenosis occurs after PTA, resulting in vascular lumen loss and a decrease in blood flow. Experimental animal models have been developed to study the pathogenesis of stenosis, but there is no restenosis model after PTA of stenotic AVF in mice. Here, we describe the creation of a murine model of restenosis after angioplasty of a stenosis in an AVF. The murine restenosis model has several advantages, including the rapid development of restenotic lesions in the vessel after angioplasty and the potential to evaluate endovascular and perivascular therapeutics for treating restenosis. The protocol includes a detailed description of the partial nephrectomy procedure to induce chronic kidney disease, the AVF procedure for development of de novo stenosis and the angioplasty treatment associated with progression of restenosis. We monitored the angioplasty-treated vessel for vascular patency and hemodynamic changes for a period of 28 d using ultrasound. Vessels were collected at different time points and processed for histological analysis and immunostaining. This angioplasty model, which can be performed with basic microvascular surgery skills, could be used to identify potential endovascular and perivascular therapies to reduce restenosis after angioplasty procedures.

Differences in Transforming Growth Factor-ß1/BMP7 Signaling and Venous Fibrosis Contribute to Female Sex Differences in Arteriovenous Fistulas.

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex-specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real-time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b), with increased transforming growth factor-ß1 (Tgf-ß1) and transforming growth factor-ß receptor 1 (Tgfß-r1). There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf-ß1, Tgfß-r1, andCol1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf-ß1 and Tgfß-r1, and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.