CEACAM1 and TNF-α in Age-Related Vascular Dysfunction
Researchers here report on their investigations of one small part of the complex biochemistry of chronic inflammation and oxidative stress that is observed in aging blood vessels. This sort of work is carried out in search of novel target proteins and mechanisms that might be influenced in order to treat age-related vascular conditions, those that arise from the downstream consequences of chronic inflammation in older individuals. It would be a better approach to address the causes of age-related chronic inflammation rather than adjust its mechanisms or immediate consequences, but this remains a less popular strategy in the research community. The quest for complete understanding of any given disease process tends to shed light on proximate causes and immediate consequences, and thus that is where most new therapeutic development is focused.
CEACAM1 contributes to angiogenesis by induction of vascular sprouting, but has not been associated with the vascular aging process until recently. It has been known for a long time that the pro-inflammatory cytokine TNF-α is upregulated within the wall of aging vasculature and contributes to endothelial dysfunction that in turn predicts cardiovascular events. Since we showed previously that CEACAM1 is critically involved in TNF-α-mediated endothelial barrier breakdown via adherens junction disassembly, we wondered whether CEACAM1 might also contribute to vascular aging.
As a first hint, we observed re-expression of CEACAM1 in the murine and human vasculature with progressive age. This upregulation of vascular CEACAM1 expression is of great importance since we demonstrated that the presence of CEACAM1 is necessary for age-associated vascular upregulation of TNF-α using a murine CEACAM1 knockout model. Reversely, TNF-α induced the expression of CEACAM1 in cultured endothelial cells, indicating the establishment of a vicious cycle within aging vessels.
A hallmark of vascular aging is the increased deposition of collagen fibers within the media of larger vessels. Intriguingly, we found that only in the presence of CEACAM1 vascular aging in mice was accompanied by vascular fibrosis presumably due to enhanced TGF-β/TGF-βR1 signaling whereas genetic deletion of CEACAM1 completely prevented aortic collagen accumulation. Age-related CEACAM1-dependent vascular collagen accumulation might increase arterial stiffness, which is known to augment cardiac afterload permanently resulting in concentric ventricular hypertrophy and cardiomyopathy.
Finally, we found that CEACAM1 contributes to the age-related increase in oxidative stress within the vasculature which promotes endothelial barrier impairment. It is well-known that oxidative stress is also critically involved in processes that promote angiopathies like atherosclerosis. Although there are some hints pointing to a role of CEACAM1 in atherosclerosis the exact contribution of CEACAM1 in these processes is yet to be defined.
In summary, we identified CEACAM1 as an important player in the process of vascular aging. Identification of mechanisms of vascular aging in detail that are regulated by endothelial and vascular presence of CEACAM1 might therefore open up new therapeutic strategies to slow-down the vascular aging process thereby reducing the risk of life-threatening cardiovascular events.