The Aging Microvasculature and Alzheimer's Disease
The microvasculature of the body diminishes with age, and this is thought to be a major contributing factor in the progression of age-related loss of organ function, particularly in energy-hungry tissues such as muscles and the brain. Every tissue is densely packed with tiny blood vessels, hundreds of capillaries passing through every square millimeter in cross-section. This small-scale microvasculature is needed in order to efficiently deliver sufficient nutrients to all cells in a tissue. Absent capillaries, perfusion of nutrients is only useful over a very short distance indeed, and its effectiveness declines quickly as that limit is approached. Unfortunately, the density of capillary networks is lost with age.
The mechanisms regulating angiogenesis, the growth and maintenance of blood vessels, are very complex, but also quite well explored as a result of their relevance to many areas of medicine. Some approaches are demonstrated to produce usefully greater regrowth of blood vessels following injury in animal studies, such as mobilization of hematopoietic cells from the bone marrow. Many of the possible points of intervention via upregulation or interdiction of a single protein result in problematic growth, however. Blood vessels grow where they should not grow, or are poorly formed, or both. Excessive angiogenesis of leaky vessels in the eye, provoked by pro-growth signals secreted by senescent cells, is a feature of macular degeneration, for example.
Nonetheless, the evidence for loss of capillary density to be important in aging is compelling. This should be motivation enough to work on ways to safely invigorate the faltering mechanisms of angiogenesis, and thereby turn back this aspect of degenerative aging, improving tissue function throughout the body by no longer starving cells of required nutrients.
Microvascular Alterations in Alzheimer's Disease
Reduced capillary density with aging is attributed to diminished levels of angiogenic growth factors (such as VEGF), an imbalance between production of angiogenic and anti-angiogenic growth factors, and reduction of nitric oxide release and impaired vasodilation. The Neuroangiogenesis Hypothesis has been proposed, wherein a decline in growth factors and angiogenic cytokines leads to a reduction in vessel density and cognition. Restoration of vessel density through administration of growth factors, such as VEGF, is proposed as a treatment to prevent development of Alzheimer's disease (AD) symptoms. In addition to vessel loss, aging is linked to increased capillary tortuosity and a thickened basement membrane. Pericytes are lost or become dysfunctional, causing blood-brain barrier dysfunction and impaired flow regulation that decreases oxygen concentration in tissue.
Vascular risk factors are prominent in aged populations. This may be due to aging-induced inflammation and cytokine release, leading to endothelial dysfunction and arterial stiffening. Hypertension is associated with microvascular abnormalities such as endothelial swelling and reduced capillary density. This microvascular deficiency in hypertension is potentially aggravated by a deficiency in circulating insulin-like growth factor 1 (IGF-1) due to aging.
The reduced vessel density at older ages might be attributable to the aging process and reduced expression of angiogenic growth factors. In brains without AD, decline in growth factors with aging, such as VEGF, fibroblast growth factor (FGF-1 and FGF-2), and angiopoietin, yield slow recovery in tissue wound injuries due to reduced angiogenic capabilities, or display reduced angiogenesis in response to hypoxia. In a human study, researchers found significant reduction in serum VEGF relative to both amnestic mild cognitive impairment and control (healthy) individuals. Transforming growth factor β1 (TGF-β1) (an angiogenic growth factor) serum concentration was reduced in AD, with the reduction in VEGF and TGF-β1 levels correlating with cognitive impairment severity. It was hypothesized that this indicates reduction in angiogenic growth factors contribute to cognitive impairment.
Due to reduced capillary density with aging, researchers proposed VEGF and growth factor administration for restoring capillary density and blood flow. A study in TgCRND8 AD mice overexpressing VEGF found partial recovery of vessel density and restoration of memory impairments, supporting enhancing vascular growth as a method for improving cognition. There are factors to consider in applying this therapy to humans. VEGF in high concentrations may induce blood-brain barrier leakage. Many newly formed vessels during angiogenesis are leaky with abnormal morphology.
Regrowth of vascular is more than increasing vessel number through administering VEGF. Newly formed vessels adjust their diameters, potentially differentiate into arteries or veins, and recruit support cells such as smooth muscle cells, pericytes, and fibroblasts to produce a functional vessel network. Expanding growth factor therapy to AD will require consideration of relative concentrations of naturally occurring growth factors unique to each subject and state of dementia, delivery method, and determining growth factors to administer.
A related therapy to growth factor administration that overcomes some deficiencies is exercise. Exercise increases concentration of a variety of angiogenic molecules such as Ang1 and Ang2, VEGF, fibroblast growth factor (FGF, upregulates VEGF, and induces vasodilation through nitric oxide), transforming growth factor (TGF, regulates extracellular matrix formation), and platelet derived growth factor (PDGF, mitogen for smooth muscle cells, fibroblasts, and glia cells). Mice provided access to running wheels demonstrated elevated brain microvascular efficiency and increased blood flow in the hippocampus.