Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations

Abstract

Background Vascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location. Angiogenic and inflammatory proteins are secreted into the bloodstream and may serve as useful biomarkers for identifying patients at risk for complications or with certain disease phenotypes. Methods A validated multiplex protein array consisting of 26 angiogenic and inflammatory biomarkers (Angiome) was assessed in plasma isolated from healthy controls and patients with either sporadic brain arteriovenous malformation (BAVM), familial cerebral cavernous malformation (CCM), or hereditary hemorrhagic telangiectasia (HHT). These samples were obtained from archives of ongoing research studies at the University of California San Francisco and through prospective collection at the Toronto HHT Centre at St. Michael’s Hospital. Results We compared circulating biomarker levels from each patient group to healthy controls and analyzed each pairwise combination of patient groups for differences in biomarker levels. Additionally, we analyzed the HHT samples to determine the association between biomarker levels and the following HHT-specific phenotypes, BAVM, pulmonary arteriovenous malformation (PAVM), liver vascular malformation (LVM), and gastrointestinal (GI) bleeding. Compared to controls, levels of SDF1 were significantly elevated in HHT patients (Proportional Increase [PI] = 1.87, p < 0.001, q = 0.011). Levels of sENG were significantly reduced in HHT patients compared to controls (PI = 0.56, p < 0.001, q < 0.001), reflecting the prevalence of HHT1 patients in this cohort. Levels of IL6 (PI = 3.22, p < 0.001, q < 0.001) and sTGFβR3 (PI = 0.70, p = 0.001, q < 0.029) differed significantly in CCM patients compared to controls. Compared to controls, ten of the biomarkers were significantly different in sporadic BAVM patients (q-values < 0.05). Among the pairwise combinations of patient groups, a significant elevation was observed in TGFβ1 in CCM patients compared to sporadic BAVM patients (PI = 2.30, p < 0.001, q = 0.034). When examining the association of circulating biomarker levels with HHT-specific phenotypes, four markers were significantly lower in HHT patients with BAVM (q-values < 0.05), and four markers were significantly higher in patients with LVM (q-values < 0.05). Conclusions This pilot study suggests that the profile of circulating angiogenic and inflammatory biomarkers may be unique to each type of vascular malformation. Furthermore, this study indicates that circulating biomarkers may be useful for assessing phenotypic traits of vascular malformations.

ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia

“…For instance, levels of ANG2 skewed higher in brain and lung AVMs but were reduced in liver AVMs when combined HHT patient data was analyzed, though this was not statistically significant or separated between the types of HHT. 72 When comparing ANG2 levels in heterozygous HHT models, pulmonary ANG2 was found to be unchanged in Eng +/− mice but increased in the lungs of Alk1 +/− mice compared to corresponding controls. 70 These studies are relevant because incidences of tissue/organ-specific AVMs differ between the various types of HHT.…”

“…71 Recently, combined measurements of circulating ANG2 from patients with the 3 major forms of HHT, although not statistically significant, trended toward a decrease in ANG2 levels. 72 Furthermore, cultured blood outgrowth ECs from ENG -HHT1 and ALK1 -HHT2 patients and several tissues from Eng +/− heterozygous mutant mice exhibited substantial decreases in ANG2 expression. 70,73 Taking these discrepancies into consideration, several explanations could account for these observed variances.…”

Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia

“…On T-helper lymphocytes, CXCR4 under-expression seems to be a central phenomenon in the idiopathic CD4 lymphopenia [ 29 ], but the infectious profiles are quite different. An alternative explanation could be a chronic elevation of the CXCL12 plasma level, described in severe infection [ 30 , 31 ] and recently in HHT [ 32 ]. Such an elevation is known to lead to continuous CXCR4 and CD26 internalization as a desensitization process [ 9 , 33 ].…”

"Recent Advances in Hereditary Hemorrhagic Telangiectasia Pathogenesis and Therapies"

“…Administration of Angpt2 monoclonal antibodies prevented and resolved retinal AVMs of Smad4 mutant mice [104] and improved brain vascular morphology in other HHT models [105]. However, other studies showed that the blood ANGPT2 levels were decreased in HHT2 patients and unchanged in HHT1 patients [106,107]. Further, cultured blood outgrowth ECs from HHT1 and HHT2 patients, along with several tissues collected from Eng +/− mice exhibited substantial decreases in Angpt2 levels [108,109].…”