Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease

Arunima Kapoor; Aimée Gaubert; Anisa Marshall; Irene B Meier; Belinda Yew; Jean K Ho; Anna E Blanken; Shubir Dutt; Isabel J Sible; Yanrong Li; Jung Yun Jang; Adam M Brickman; Kathleen Rodgers; Daniel A Nation

doi:10.3389/fnagi.2021.711784

Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease

Front Aging Neurosci. 2021 Sep 28:13:711784. doi: 10.3389/fnagi.2021.711784. eCollection 2021.

Authors

Arunima Kapoor¹, Aimée Gaubert², Anisa Marshall³, Irene B Meier^{4

5}, Belinda Yew³, Jean K Ho², Anna E Blanken³, Shubir Dutt³, Isabel J Sible³, Yanrong Li², Jung Yun Jang², Adam M Brickman⁴, Kathleen Rodgers⁶, Daniel A Nation^{1

2}

Affiliations

¹ Department of Psychological Science, University of California, Irvine, Irvine, CA, United States.
² Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States.
³ Department of Psychology, University of Southern California, Los Angeles, CA, United States.
⁴ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States.
⁵ Chione GmbH, Binz, Switzerland.
⁶ Center for Innovation in Brain Science, Department of Pharmacology, The University of Arizona, Tucson, AZ, United States.

Abstract

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55-90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (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, and 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 × 10⁵, 95% CI (0.2, 1.9), p = 0.019], 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 = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. 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 SVD.

Keywords: aging; cerebral microvascular pathology; cerebral small vessel disease; dementia; endothelial progenitor cells; vascular dementia; vascular endothelial growth factor.

Abstract

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