Capillary Basement Membrane Thickness in Health and Disease

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TEM studies of CBMs in humans and other vertebrates show that regardless of animal age or health, they are continuous along the length of the microvessel and closely adhere to their parent cell types as described previously. CBM thickness, however, is widely variable within and between tissue types both in health and disease.

It is now clear that in many tissues, CBM thickness is a normal function of age and is considered a biomarker for aging. However, thickness increases with age are not seen in all tissues and all animal models, and few rigorous studies have been carried out to address this issue. Nevertheless, most investigators believe modest increases in CBM thickness are a normal age-related process. In certain disease states, however, CBM thickening is excessive and is considered a diagnostic hallmark. This is especially true in chronic stages of diabetes mellitus where most CBMs are thickened, and glomerular and retinal CBMs show remarkable thickness increases in humans and animal models of the disease [2]. In fact, it is fair to say that most CBM thickness studies have been carried out in diabetics in an effort to identify possible patterns that could point to potential molecular regulators of BM thickening. Of these investigations, a large percentage has focused on capillaries in the retina and renal glomerulus, where their diabetic sequelae often lead to retinal degeneration and blindness and/or renal decompensation and death. Moreover, because diabetes often has been cited as a disease of premature aging, recent studies have sought metabolic mechanisms that might possibly explain both normal, benign, age-related CBM thickness increases as well as those of diabetic BM disease.

Several mechanisms are implicated in the pathogenesis of microangiopathy leading to diabetic CBM thickening. These have been reviewed recently [3] and include hyper-glycemia-induced increases in Type IV collagen synthesis, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased tissue inhibitors of metalloproteinase (TIMP). Vascular endothelial growth factor (VEGF) also may be involved because treatment with anti-VEGF antibodies reduces glomerular BM thickening. Also, oxygen radicals/oxidative stress and advanced glycation end products (AGEs) may play a role because aminoguanidine (which inhibits AGE formation, but also has antioxidant properties) attenuates diabetic nephropathy. In addition, the polyol enzymatic pathway is stimulated by hyperglycemia and has been implicated in the chronic sequelae of diabetes. In this regard, hyperpermeability is an early feature of diabetic microangiopathy and is reduced by aldose reductase inhibitors. Because hyperglycemia apparently increases the generation of reactive oxygen species (ROS), activates aldose reductase, and induces AGE-formation, it has been postulated that ROS production may represent a common underlying element in several pathways leading to diabetic microvascular damage, including increased CBM thickness.

Clearly, CBM thickness is an important parameter in a wide variety of biological and medical investigations. Moreover, because thickness changes necessarily alter CBM functional capacities, it is important to accurately measure their physical dimensions in order to identify patterns of change that might offer insights into molecular mechanisms regulating their form and function.

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