Decreased Levels of Angiogenic Growth Factors in Intracranial Atherosclerotic Disease despite Severity-Related Increase in Endothelial Progenitor Cell Counts

Abstract

Background: Intracranial atherosclerotic disease (ICAD) is an important cause of ischemic stroke (IS) and endothelial dysfunction plays a critical role in its onset and progression. Endothelial progenitor cells (EPCs) and endothelial production of angiogenic growth factors (AGFs) may play an essential role in this process. This study investigated the association of EPCs and AGFs with ICAD severity. Methods: A total of 42 patients who had experienced a transient ischemic attack (TIA) or IS attributable to symptomatic ICAD were included. Clinical and neurosonological evaluations were conducted between 2.4 and 8.7 years after the initial cerebrovascular event. Severe ICAD was defined as the presence of at least 1 severe intracranial stenosis, and extensive ICAD as 3 or more intracranial stenoses. Blood samples were obtained to determine EPC levels using flow cytometry (CD34+KDR+ cells), and the plasma levels of several growth factors were assessed with a protein array (Searchlight^®). Twenty-two individuals without cerebrovascular disease and with normal ultrasonographic examination were also included. Results: No difference in the count of circulating EPCs was found between patients and controls, and a moderate increase in the number of EPCs/ml was noted in patients with extensive ICAD (p = 0.05). Patients presented decreased levels of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF-BB) compared with controls (p = 0.002, p = 0.079 and p = 0.061, respectively). Higher levels of FGF, VEGF and PDGF-BB were found in patients with severe ICAD (p = 0.007, p = 0.07 and p = 0.07, respectively), but there was no correlation between any AGFs and EPCs. Conclusions: Symptomatic ICAD patients have decreased levels of AGFs with no correlation to the number of circulating EPCs, while patients with severe ICAD have higher levels of EPCs, FGF, VEGF and PDGF-BBs. This suggests that reduced EPC and proangiogenic factor production capacity is implicated in ICAD pathogenesis, while the more severe forms of chronic brain hypoperfusion in ICAD patients might stimulate EPC mobilization and AGF production.