The Role of Angiogenesis in Haemophilic Arthropathy: Where Do We Stand and Where Are We Going?

Agapidou, Alexandra; Stavrakis, Thomas; Vlachaki, Efthymia; Anagnostis, Panagiotis; Vakalopoulou, S.

doi:10.4274/tjh.2016.0031

Cited by 7 publications

(5 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Angiogenesis is known to occur mainly in the bone marrow and vascular stem cells. Studies have reported that angiogenic factors such as VEGF, ANG‐1, ANG‐2, and fibroblast growth factor participate in endothelial cell proliferation 13 . It was previously reported that serum concentrations of VEGF, VEGFR, ANG‐1, and Fms‐like tyrosine kinase‐1 are associated with inflammatory markers and bone resorption in patients with haemophilia 3 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, increase in angiogenic factor levels was corroborated by a corresponding increase in mRNA expression of ENG, HIF-1A, PGE-2, and VEGFA.Studies on animal models and cell cultures have established the role of ENG in vascular development and tumour angiogenesis. Since high-degree of neo-angiogenesis and aberrant vascular remodelling are thought to underlie the pathogenesis in haemophilic arthropathy,13 we set out to investigate the mRNA expression and protein levels of ENG in haemophilia patients. Despite not having active bleeds at the time of sample withdrawal, both ENG mRNA expression and ENG protein were elevated in haemophilia patients compared to control subjects, suggesting that chronic inflammatory conditions might induce a continuous state of neo-angiogenesis and joint damage.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Increased endoglin levels correlated with angiogenesis‐associated angiopoietin‐2 in haemophilia patients

et al. 2021

View full text Add to dashboard Cite

Haemophilia is a bleeding disorder that occurs due to the deficiency of coagulation factors, and the angiogenesis process is an important process underlying the pathophysiology of haemophilic arthropathy. The role of the new adipocytokine endoglin (ENG) in patients with haemophilia is not yet known. Aim:The aim of this study is to evaluate the association between ENG protein and angiogenesis-related cytokines in patients with haemophilia for the first time.Methods: Plasma protein levels and mRNA expressions of ENG and various angiogenesis-associated cytokines were compared in blood samples collected from 28 patients with haemophilia A or B and 29 healthy volunteers. The relationship between the cytokines and ENG were determined by correlation analysis.Results: Plasma ENG levels and angiogenic markers were found to be significantly higher in patients with haemophilia compared to controls. Real-time PCR studies showed that mRNA expressions of ENG, vascular endothelial growth factor A, hypoxiainducible factor A, and prostaglandin E2 increased in patients with haemophilia.Correlation analysis showed a significant positive correlation between ENG and angiopoietin-2 levels in the haemophilia group. Besides, a significant decrease in annexin-V binding to platelets in haemophilia patients compared to control was found to be related to the bleeding profiles in the patients. Conclusions:This study determined that ENG protein may be involved in the formation of angiogenesis in haemophilia patients and its effects may be related to angiogenetic marker angiopoietin-2 in this process. Our findings contribute to the literature during the determination of target proteins in haemophilia treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Increased endoglin levels correlated with angiogenesis‐associated angiopoietin‐2 in haemophilia patients

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Therefore, it is important to evaluate the pathogenesis of hemophilic arthropathy and attempt new targeted therapies [11]. VEGF plays an essential role in the pathogenesis of hemophilic arthropathy [3]. Because of such involvement, we aimed to determine whether inhibiting VEGF with intra-articular bevacizumab would also inhibit neoangiogenesis and reduce cartilage damage and synovial changes in a rabbit model of hemophilic arthropathy.…”

Section: Discussionmentioning

confidence: 99%

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Mert

Bılgıç

Şenol

et al. 2023

Clin Orthop Relat Res

View full text Add to dashboard Cite

Background Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Questions/purposes Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Methods Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits’ ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Results Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). Conclusion Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. Clinical Relevance If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled.

show abstract

“…In detail, type A synoviocytes, after incorporating iron, produce inflammatory cytokines (IL-1β, IL-6, TNFα), in turn inducing migration of polymorphonuclear cells and, later, of monocytes and lymphocytes. This leads to a self-maintaining cycle further increasing inflammatory response and inducing an enhanced angiogenesis (Lafeber et al, 2008;Agapidou et al, 2016). Indeed, the inflamed and hypertrophic synovium has an enhanced oxygen demand, stimulating both locally and systemically the release of growth factors like vascularderived endothelial growth factor (VEGF), thus promoting neoangiogenesis (Pulles et al, 2017).…”

Section: Iron Chemical Damage In Synovitis (Figure 1)mentioning

confidence: 99%

Pathophysiological Role of Synovitis in Hemophilic Arthropathy Development: A Two-Hit Hypothesis

et al. 2020

View full text Add to dashboard Cite

Despite an increasing access to prophylaxis with clotting factor concentrates, arthropathy still represents the main chronic complication of hemophilia. Whereas previous studies described hemophilic arthropathy (HA) as a degenerative arthropathy, somehow resembling osteoarthritis (OA), most recent evidence suggests that complex inflammatory and immunologic mechanisms are also involved in the pathophysiology of HA. In the present review, we described available data on major mechanisms leading to arthropathic changes in patients with hemophilia, with a specific focus on the role of synovium. The presence of hemosiderin in the joint space induces synovium proliferation, thus leading to formation of several lytic enzymes determining chondrocytes apoptosis and proteoglycans levels reduction. This leads to a direct joint "chemical" damage representing early damages in the pathogenesis of HA (first hit). In parallel, synovial membrane and synovial endothelial cells become a dynamic reservoir of inflammatory cells and mediators, and propagate the inflammatory response (second hit), switching the process from a chemical damage to an inflammatory damage. Overall, consistent data pointed out synovitis as the keystone in HA pathophysiology. This opens novel potential therapeutic targets in this clinical setting.

show abstract

The Role of Angiogenesis in Haemophilic Arthropathy: Where Do We Stand and Where Are We Going?

Cited by 7 publications

References 38 publications

Increased endoglin levels correlated with angiogenesis‐associated angiopoietin‐2 in haemophilia patients

Increased endoglin levels correlated with angiogenesis‐associated angiopoietin‐2 in haemophilia patients

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Pathophysiological Role of Synovitis in Hemophilic Arthropathy Development: A Two-Hit Hypothesis

Contact Info

Product

Resources

About