Aging is associated with impaired angiogenesis, a process crucial for maintaining healthy tissues and organs. This impairment contributes to age-related diseases, especially cardiovascular issues. Exercise has been shown to improve overall health and has demonstrated positive effects on angiogenesis in various populations. However, the mechanisms underlying the beneficial effects of exercise on angiogenesis in older adults remain unclear. This study aimed to systematically review and meta-analyze the effects of exercise on multiple peripheral blood angiogenesis markers in older adults (≥50 years) to better understand this relationship. The study hypothesized that regular exercise would lead to favorable changes in the concentrations of these markers, reflecting improved angiogenesis. This is crucial because understanding how exercise impacts angiogenesis could lead to targeted interventions to combat age-related decline and improve overall health in older adults. The inconsistent findings from previous studies regarding the impact of exercise on angiogenesis markers highlight the need for a comprehensive meta-analysis to clarify the overall effect. Such a study would inform the development of evidence-based exercise recommendations for improving cardiovascular health and overall well-being in aging populations.

The literature review explored the roles of several angiogenesis markers including vascular endothelial growth factor (VEGF), endostatin, e-selectin (CD62E), fibroblast growth factor 2 (FGF2), and matrix metallopeptidase-9 (MMP9). VEGF is a crucial pro-angiogenic factor, promoting blood vessel formation. Endostatin, conversely, is an anti-angiogenic factor. E-selectin's role in angiogenesis is less clear but it has been suggested to regulate the anti-angiogenic activity of other factors. MMP9 is a pro-angiogenic factor involved in extracellular matrix remodeling but also plays a role in generating the anti-angiogenic factor, angiostatin. Studies showed that these markers change with age, with VEGF and FGF2 levels potentially decreasing, while matrix metalloproteinases may increase. This age-related alteration in angiogenesis markers correlates with a higher risk of cardiovascular diseases. Existing research on exercise and angiogenesis is inconsistent, lacking a meta-analysis focusing on multiple markers in healthy older adults. This prompted the current study to comprehensively examine the exercise effects on various blood angiogenesis markers in this population.

This systematic review and meta-analysis followed the PRISMA guidelines and was registered on the International Prospective Register of Systematic Reviews. The search included MEDLINE, Embase, and Cochrane CENTRAL databases (March 10, 2022) using key terms related to exercise and angiogenesis markers. Inclusion criteria involved healthy older adults (≥50 years), measurement of serum/plasma concentrations of selected angiogenesis proteins before and after moderate-intensity exercise, and exclusion of individuals with comorbidities. Two independent reviewers assessed study selection and risk of bias using adapted criteria from the Newcastle Ottawa Scale and the Cochrane Collaboration's Risk of Bias Assessment Tool. Data extraction included means and standard deviations of angiogenesis protein concentrations, population characteristics, exercise intervention details, and risk of bias items. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity was assessed using the I² statistic and Q statistics. Meta-regressions and subgroup analyses were performed to investigate heterogeneity based on exercise type, duration, population characteristics (healthy, overweight, obese), blood compartment, and risk of bias. Publication bias was assessed using Egger's test, funnel plots, and trim-and-fill. Data analysis was conducted using STATA 17.0. For the meta-analysis, at least three studies were needed for each protein of interest.

The literature search yielded 9288 records, with 44 articles meeting the inclusion criteria and sufficient data. Of these, 38 were included in meta-analyses for five proteins: VEGF, endostatin, CD62E, FGF2, and MMP9. Meta-analyses revealed significantly higher VEGF levels after exercise (SMD [95% CI] = 0.18 [0.03, 0.34], p = 0.02) and significantly lower CD62E levels after exercise (SMD [95% CI] = -0.72 [-1.42, -0.03], p = 0.04). No significant changes were observed for endostatin, FGF2, or MMP9. Significant heterogeneity was detected for VEGF and CD62E. Subgroup analyses explored heterogeneity based on exercise type (aerobic vs. resistance), duration, population characteristics (healthy vs. overweight/obese), blood compartment (serum vs. plasma), and risk of bias. Meta-regressions investigated associations between VEGF changes and age, sex, exercise dose, BMI, and VO2max, showing no significant relationship. Qualitative synthesis included 17 angiogenesis markers; ANGPTL4 and TSP-1 showed a significant increase after exercise, while others showed non-significant trends toward increases or decreases.

The findings suggest that exercise influences specific angiogenesis markers in older adults. The increase in VEGF aligns with its role in promoting angiogenesis. The decrease in CD62E might be related to its suggested anti-angiogenic actions. However, the lack of significant changes in other markers suggests that the effect of exercise on angiogenesis is complex and may involve multiple pathways. The heterogeneity in the results warrants caution, potentially due to variations in study designs, exercise protocols, and populations. The small number of studies for some markers (endostatin, FGF2, MMP9) limits the generalizability of the findings. Furthermore, the observed changes in VEGF and CD62E could potentially reflect effects beyond angiogenesis, such as inflammation, as both have inflammatory properties. Overall, the findings support the idea that exercise can induce changes in blood markers relevant to angiogenesis, but more research is needed to elucidate the specific mechanisms and long-term effects. The association with exercise type and duration should be further explored.

This meta-analysis demonstrates that exercise induces changes in some angiogenesis markers in healthy older adults, namely VEGF and CD62E. VEGF levels increased after exercise, potentially depending on the exercise type, blood compartment, and population. CD62E levels decreased, potentially depending on the exercise duration and blood compartment. The limited number of studies for several other markers highlights the need for future research to explore a wider range of angiogenesis markers and to fully understand the relationship between exercise and angiogenesis in older adults. Future studies should also consider the duration of effects and the impact of factors like hydration on the results.

Several limitations affect the interpretation of these findings. The small number of studies for some angiogenesis markers limited statistical power and generalizability. Significant heterogeneity across studies suggests that factors such as exercise parameters, demographics, and measurement protocols influence the response to exercise. Publication bias was a concern, particularly for VEGF. The observed changes in markers may not be solely related to angiogenesis but could reflect other physiological changes, like inflammation. The lack of detailed information regarding hydration in the included studies prevents assessment of its potential impact.