Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke

Abstract

Angiogenesis is an important pathophysiological response to cerebral ischemia, and can be modulated by vascular endothelial growth factor (VEGF) and endostatin. Circulating endothelial progenitor cells (EPCs) also play an important role as an endogenous repair mechanism for ischemic injury. We sought to investigate early changes in the expression of VEGF and endostatin in serum and the circulating EPCs in patients with acute ischemic stroke (AIS) and analyzed the relations between them. The peripheral blood and serum samples were obtained from 30 patients at 1, 3, 5 and 7 d after AIS. Flow cytometry was used to quantify EPCs, and VEGF and endostatin were measured by enzyme linked immunosorbent assay. Correlation analysis was performed to assess the relations between them. Receiver operating characteristic (ROC) curve was used to appraise the value of EPCs levels in predicting the 90-day prognosis after AIS. Compared with control subjects, circulating EPCs numbers increased from a very lower initial level (P < 0.001) until 7 d after AIS. Serum VEGF and endostatin levels increased and peaked at 3 d and 5 d post-stroke (both P < 0.001), respectively. A significant correlation (P = 0.001) was found between peak serum VEGF concentration and peak endostatin concentration. VEGF/endostatin ratio at day 1 and day 3 after AIS significantly correlated with circulating EPCs numbers at day 5 (P < 0.001) and day 7 post-stroke (P < 0.001). ROC curve analysis suggested that circulating EPCs number at day 7 had a significantly predictive power for good prognosis. VEGF and endostatin may mediate EPCs proliferation in the early phase of ischemic stroke, and the circulating EPCs levels can be a predictor of clinical outcome in AIS.

Circulating levels of vascular endothelial growth factor and post‐stroke long‐term functional outcome

“…A similar pattern of elevation of s‐VEGF was shown in two relatively small studies that included both IS and hemorrhagic strokes (N = 52 and N = 33), with no association to improvement in the National Institutes of Health Stroke Scale (NIHSS) scores after 1 week, or in the Stroke Impairment Assessment Set (SIAS) at discharge approximately 3 months post‐stroke . In another study (N = 30), the s‐VEGF levels appeared to be more dynamic, with a plateau phase until Day 7 after an initial increase on Day 1‐3 . Interestingly, in a recent study (N = 83), high s‐VEGF levels 7 days after IS correlated significantly with better functional outcome (mRS 0‐2) after 3 months, although it was not examined whether baseline stroke severity or IS subtype affected these associations.…”

“…Thus, an elevated s‐VEGF, due to for example systemic inflammation, may reach the brain more readily due to BBB dysfunction in IS. Furthermore, there is a need to include control groups, preferably consisting of age‐ and sex‐matched healthy subjects as well as measurements at several time‐points to evaluate s‐VEGF and its changes in IS, which has not been performed in some previous studies . In contrast, our study has a large sample size, a population‐based control group of similar age and gender distribution as the IS patients, and measurements of s‐VEGF at two time‐points.…”

“…In patients with IS, in line with the experimental findings, endogenous serum VEGF (s‐VEGF) has shown variable responses to IS, and the associations with functional outcomes have differed between studies . These discrepancies may be attributable to the relatively small study cohorts with lower statistical power, biased selection of specific stroke types, or short follow‐up periods.…”

“…13 In another study (N = 30), the s-VEGF levels appeared to be more dynamic, with a plateau phase until Day 7 after an initial increase on Day 1-3. 10 Interestingly, in a recent study (N = 83), high s-VEGF levels 7 days after IS correlated significantly with better functional outcome (mRS 0-2) after 3 months, 8 although it was not examined whether baseline stroke severity or IS subtype affected these associations. Similarly, although the absolute functional outcome levels were not presented, high s-VEGF levels at 24 hours post-stroke were independently associated with a more marked improvement in NIHSS scores up to 3 months in IS patients with large vessel disease or small vessel disease (N = 180).…”

“…In patients with IS, in line with the experimental findings, endogenous serum VEGF (s-VEGF) has shown variable responses to IS, and the associations with functional outcomes have differed between studies. [6][7][8][9][10][11][12][13][14] These discrepancies may be attributable to the relatively small study cohorts with lower statistical power, biased selection of specific stroke types, or short follow-up periods. For example, s-VEGF was significantly increased in patients with acute IS (N = 29) at 0-7 days post-stroke compared to healthy controls without any clear day-to-day changes in s-VEGF.…”