Elastin Fragmentation and the Elastin Receptor Complex in Aging Blood Vessels
Elastin is a vital component of the complex structure of the extracellular matrix in flexible, elastic tissues, such as skin and blood vessel walls. It is the extracellular matrix that determines physical tissue properties, such as strength, elasticity, and so forth. This structure becomes disarrayed with age for a variety of reasons: photoaging that breaks down molecules or encourages alterations; cross-linking between molecules that restricts their range of motion; changes in the behavior of cells that maintain the structure.
Today's open access paper looks at a different aspect of this issue. The researchers discuss what happens to the debris from elastin that is broken down, and how cells react to this signal of damage. Unfortunately, further harms resulting from initial damage are very much a characteristic of aging. It isn't just that molecules become broken, but cells then change their behavior as a result, often in maladaptive ways.
Restoration of the extracellular matrix in aged tissues is one of the areas of rejuvenation research in which there is little forward motion, and there are too many goals here for which there are, as of yet, no good, obvious approaches to therapy ready to move into preclinical development. Cross-links can in principle be broken, but only one biotech company is working on a plausible approach applicable to the whole body at present. Cells can be reprogrammed to more youthful function, but it is unclear as to whether that will result in improved maintenance of skin extracellular matrix in the context of damage and disarray that is not present in youth. Cells can be coerced into elastin deposition, such as via minoxidil use, but there are no good ways of doing this systemically that do not result in untenable side-effects. And so forth. More attention is needed in this part of the field.
The Elastin Receptor Complex: An Emerging Therapeutic Target Against Age-Related Vascular Diseases
Aging is accompanied by changes in vascular structure and function, especially in the large arteries. Due to their elasticity and resilience capacities, the concentric elastic lamellae of the aorta play a pivotal role in reducing the high systolic pressure at the outlet the heart. In other words, elastic lamellae stretch during cardiac ejection phases allowing the radius of the aorta to increase and to convert the pulsatile flow leaving the heart into a continuous flow in arteries. With age, these elastic lamellae exhibit wear characterized by zones of rupture. This leads to loss of elasticity and progressive hardening of the aorta and release of elastin-derived peptides (EDPs) in the circulating blood.
Elastic fibers fragmentation and release of elastin degradation products, also known as elastin-derived peptides (EDPs), are typical hallmarks of aged conduit arteries. Along with the direct consequences of elastin fragmentation on the mechanical properties of arteries, the release of EDPs has been shown to modulate the development and/or progression of diverse vascular and metabolic diseases including atherosclerosis, thrombosis, type 2 diabetes, and nonalcoholic steatohepatitis.
Most of the biological effects mediated by these bioactive peptides are due to a peculiar membrane receptor called elastin receptor complex (ERC). This heterotrimeric receptor contains a peripheral protein called elastin-binding protein, the protective protein/cathepsin A, and a transmembrane sialidase, the neuraminidase-1 (NEU1). In this review, after an introductive part on the consequences of aging on the vasculature and the release of EDPs, we describe the composition of the ERC, the signaling pathways triggered by this receptor, and the current pharmacological strategies targeting ERC activation.
Ironically repairing the colalgen/extracellular matrix has an immediate path to monetization. Too bad nothing worthy of phase I is visible on the horizon.