Contributions of Aging to Cerebral Small Vessel Disease

Abstract

Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the face of this health challenge, the basic biology, pathogenesis, and determinants of SVD are poorly defined. This review summarizes recent progress and concepts in this area, highlighting key findings and some major unanswered questions. We focus on phenotypes and mechanisms that underlie microvascular aging, the greatest risk factor for cerebrovascular disease and its subsequent effects.

Keywords: blood-brain barrier; cerebral blood flow; endothelium; microcirculation; nitric oxide.

Figure 1.

Schematic summarizing effects of aging, vascular risk factors, and disease modifiers for SVD (small vessel disease), followed by changes in the vasculature and consequences of these changes for brain health.

Figure 2.

Schematic illustrating segments of the pial and parenchymal microcirculations, with major changes in each segment during SVD. The illustration is based on features of the human cortical microcirculation (136), with specific characteristics based on the following references (, , , , –52, 63, 71, 87, 89, 94, 102, 104, 109, 115, 137). See text for discussion and additional details.

Figure 3.

Summary of diverse effects exerted by endothelial cells in relation to vascular tone, the blood-brain barrier (BBB), thrombosis, vascular structure, neurons, and glia.

Figure 4.

Several major mechanisms that have been implicated in vascular aging. The renin-angiotensin-aldosterone system (RAAS) produces angiotensin II (Ang II) from angiotensinogen (AGT) via enzymatic actions of renin and angiotensin-converting enzyme (ACE). In addition to activating the Ang II type 1 receptor (AT1R), Ang II can stimulate production of aldosterone (Aldo), which acts via the mineralocorticoid receptor (MR). Both Aldo and Ang II promote oxidative stress by activating a Nox2 containing NADPH oxidase which produces superoxide anion. Superoxide reacts readily with NO to form peroxynitrite (ONOO⁻), with inhibitory effects on mitochondrial SOD (SOD2) and prostaglandin I₂ synthase (PGIS) due to effects on tyrosine residues. Superoxide can also be converted to H₂O₂ by SOD, and H₂O₂ can be converted to hydroxyl radical (OH·) in the presence of Fe²⁺. Via the AT1R, Ang II can activate NF-κB promoting inflammatory signaling, stimulate mitochondria to produce superoxide, or increase activity of Rho kinase (ROCK) via effects on RhoGEF. In addition to increasing vascular tone directly (not shown), ROCK inhibits production of NO by eNOS. ROCK is also activated by the endothelin-1 (ET1) pathway, where prepro-ET1 is produced from the ET1 gene (EDH1) and formed by endothelin-converting enzyme (ECE) from big-ET1. ET1 can then activate ET1 receptors (ETAR or ETBR, the latter of which can activate RhoGEF in vascular muscle). Activity of eNOS can be inhibited by ADMA (asymmetric dimethylarginine) or ADMA can be degraded by dimethylarginine dimethylaminohydrolase (DDAH). For clarity, the boxes on the right summarize related pleiotropic effects of three key molecules in this context: NO, PPARγ, and Ang II.