UC Irvine

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive and insidious damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated circulating endothelial progenitor cell (EPC) levels are observed in response to vascular injury and may represent a vascular protective mechanism. Pro-angiogenic signaling proteins may similarly be elevated with increasing damage to cerebral microvasculature. We aimed to quantify circulating EPCs and examine circulating levels of proangiogenic proteins in older adults with evidence of SVD.

Method: Independently-living older adults (ages 55-90) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes.

Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden (β = 1.0 x 105, 95% CI [0.2, 1.9], p = .019), after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex (β = .001, 95% CI [0.000, 0.001], p = .048).

Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults with no history of clinical stroke or dementia. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in cerebral SVD.