The aging of the vasculature has detrimental effects on organs throughout the body. The most structurally apparent issue is that of atherosclerosis, the buildup of fatty deposits that narrow and weaken blood vessels. This ultimately leads to heart failure, stroke, heart attack, and death. A close second is the stiffening of blood vessels, due to a variety of processes such as cross-linking to reduce elasticity in blood vessel walls, and inflammation-linked disruption of the vascular smooth muscle tissue responsible for contraction and dilation of blood vessels. This stiffening causes raised blood pressure, which in turn produces pressure damage in sensitive tissue throughout the body, and raises the risk of atherosclerotic lesions rupturing.
Further, and separately, the density of capillary networks is reduced with age. Hundreds of capillaries pass through every square millimeter of tissue cross-section in muscle alone, necessary to provide sufficient nutrients in an environment in which perfusion based transport is limited to a millimeter of distance at most. The dysfunctions of age cause a declining maintenance of these small scale blood vessel networks, which is thought to impair cell and tissue function by limiting the supply of nutrients.
In today's research, scientists attempt to address this problem via upregulation of VEGF expression, using a gene therapy approach. VEGF levels decline with age, and this is thought to be involved in the reduction in capillary network maintenance, though this layer of regulation of activity is some distance downstream from root causes of age-related change. In effect, upregulation is a compensatory approach, overriding some of the normal reaction of the molecular damage of aging.
It is interesting that this works well in mice, as a major challenge in controlling the processes of angiogenesis, the name given to the creation of new blood vessels, is that these processes are very complex. Different signals and cells are involved in different roles and different amounts at different stages, and bluntly upregulating just one component part of it tends to result in a poor outcome, such as the generation of incompletely constructed, leaky blood vessels. This is in fact what happens in wet macular degeneration, a matter of excessive malformed blood vessel growth in the retina due to the localized presence of too much VEGF, one of the peculiarities of this age-related condition. Biochemistry is complicated, and the details of any intervention matter!
All body cells rely on blood vessels (BVs) for the provision of oxygen and other blood-borne substances and, in certain settings, also for the provision of endothelial-derived paracrine factors. Like other organ systems, the vascular system undergoes aging, which leads to progressive functional deterioration. Given the centrality of BVs to organ homeostasis, it has been hypothesized that vascular aging is an upstream, founding factor in organismal aging, but experimental support for this proposition is limited. Vascular aging involves both large and small vessels, with the latter marked by capillary rarefaction, i.e., age-related failure to maintain adequate microvascular density (MVD). A key homeostatic mechanism preventing MVD reduction relies on the angiogenic activity of vascular endothelial growth factor (VEGF), which by virtue of its hypoxic inducibility, constantly acts to replenish lost vessels and match vascular supply to the tissue needs. The reasons that VEGF fails to do so during aging is unknown.
Compromised vascular function is expected to perturb organ homeostasis in ways conducive for the development of age-related frailties and diseases. Accordingly, counteracting critical facets of vascular aging might be a useful approach for their alleviation. The presumption that insufficient vascular supply in aging is underlined by VEGF signaling insufficiency, primarily (but not exclusively) because of its indispensable role in preventing capillary loss, led us to investigate whether securing a young-like level of VEGF signaling might rectify capillary loss and its sequelae. On the premise that deteriorated vascular function is an upstream driver of multiorgan malfunctioning, it is envisioned that its rectification might confer comprehensive geroprotection.
Although VEGF production is not significantly reduced during mouse aging, longitudinal monitoring revealed that VEGF signaling was greatly reduced in multiple key organs. This was associated with increased production of soluble VEGFR1 (sVEGFR1) generated through an age-related shift in alternative splicing of VEGFR1 mRNA and its activity as a VEGF trap. A modest increase of circulatory VEGF using a transgenic VEGF gain-of-function system or adeno-associated virus (AAV)-assisted VEGF transduction maintained a more youthful level of VEGF signaling and provided protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.