Key biomarkers in cerebral arteriovenous malformations: Updated review

Abstract

The formation of vascular networks consisting of arteries, capillaries, and veins is vital in embryogenesis. It is also crucial in adulthood for the formation of a functional vasculature. Cerebral arteriovenous malformations (CAVMs) are linked with a remarkable risk of intracerebral hemorrhage because arterial blood is directly shunted into the veins before the arterial blood pressure is dissipated. The underlying mechanisms responsible for arteriovenous malformation (AVM) growth, progression, and rupture are not fully known, yet the critical role of inflammation in AVM pathogenesis has been noted. The proinflammatory cytokines are upregulated in CAVM, which stimulates overexpression of cell adhesion molecules in endothelial cells (ECs), leading to improved leukocyte recruitment. It is well‐known that metalloproteinase‐9 secretion by leukocytes disrupts CAVM walls resulting in rupture. Moreover, inflammation alters the angioarchitecture of CAVMs by upregulating angiogenic factors impacting the apoptosis, migration, and proliferation of ECs. A better understanding of the molecular signature of CAVM might allow us to identify biomarkers predicting this complication, acting as a goal for further investigations that may be potentially targeted in gene therapy. The present review is focused on the numerous studies conducted on the molecular signature of CAVM and the associated hemorrhage. The association of numerous molecular signatures with a higher risk of CAVM rupture is shown through inducing proinflammatory mediators, as well as growth factors signaling, Ras‐mitogen‐activated protein kinase‐extracellular signal‐regulated kinase, and NOTCH pathways, which are accompanied by cellular level inflammation and endothelial alterations resulting in vascular wall instability. According to the studies, it is assumed that matrix metalloproteinase, interleukin‐6, and vascular endothelial growth factor are the biomarkers most associated with CAVM and the rate of hemorrhage, as well as diagnostic methods, with respect to enhancing the patient‐specific risk estimation and improving treatment choices.

Increased Collagen I/Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse

“…Since it was shown that GPNMB + macrophages may contribute to collagen synthesis in part through activating fibroblasts [ 3 , 14 , 15 ], we analyzed whether PLX5622 treatment affects GPNMB + macrophages. We found that PLX5622 treatment not only reduced the CD68 + microglia/macrophages ( p = 0.048, Figure 6 A,B) but also reduced the number of GPNMB + macrophages in the bAVMs ( p = 0.042, Figure 6 C,D).…”

“…Gluycoprotein nonmetastatic B (GPNMB) + monocytes were also identified in human bAVMs [ 12 ], which contribute to SMC depletion [ 12 ]. These cells may also be involved in collagen synthesis in part through activating fibroblasts [ 3 , 14 , 15 ]. Further, it was shown that the crosstalk of platelets with macrophages and fibroblasts aggravates inflammation and aortic wall stiffening [ 16 ].…”

Increased Collagen I/ Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse

“…Since it was shown that GPNMB + macrophages may contribute to collagen synthesis in part through activating fibroblasts [3,14,15], we analyzed whether PLX5622 treatment affects GPNMB + macrophages. We found that PLX5622 treatment not only reduced the CD68 + microglia/macrophages (p = 0.048, Figure 6A,B) but also reduced the number of GPNMB + macrophages in the bAVMs (p = 0.042, Figure 6C,D).…”

The role of key biomarkers in lymphatic malformation: An updated review

“…They are targets for the development of novel therapeutics and can be used for disease diagnosis and monitoring the progression of the disease and its response to treatment 8,16 . In a recent study, we highlighted the biomarkers most associated with cerebral arteriovenous malformations and the rate of hemorrhage 17 …”