|
Extrinsic vascular senescence triggers | |
(i) High blood cholesterol levels | [17] |
(ii) Inflammatory cytokines and growth factors |
(iii) Angiotensin II |
(iv) Hyperglycemia and associated AGEs |
|
Intrinsic vascular senescence triggers | |
(i) Telomere shortening | [17] |
(ii) Activation of Ras pathway |
(iii) Mytochondrial dysfunction, mtDNA mutations, and/or release of mitochondria-specific ROS | [18] |
|
Activated (↑) and inactivated (↓) molecular pathways and functions | |
(i) Involvement of several genes (e.g., Klotho) and proteins (e.g., Sirtuins, progerin, JunD, p66shc, and β-amyloid peptides) | [3] |
(ii) ↑ DNA damage signaling |
(a) ↑ cyclin-dependent kinase inhibitors (p15, p16, p21, p27, and/or p53) |
(b) ↓ mediators of cell cycle progression (cyclin-dependent kinase inhibitor 2A; cyclin-dependent kinases (1, 2, 4, and 6) and cyclins (A, E, and D)) |
(c) ↓ tumor suppressor RB |
(iii) ↑ nuclear factor NF-κB and CCAAT/enhancer-binding protein-β pathways | [3, 21] |
(iv) ↑ SASP program, which includes the secretion of IL-6, IL-8, chemokines, and activators of macrophages and monocytes (MCP, MIP, TNF-α, TGF-β, and GM-CSF), as well as ECM proteases | [3, 21] |
(v) ↑ procalcific factors (RUNX-2, alkaline phosphatase, collagen I, matrix GLA protein, and BMP-2) in SMCs | [12, 22] |
(vi) Impairment of eNOS and prostacyclin pathways in senescent ECs | [14, 24–26] |
(vii) Association between decreased levels of CDKN1 and CDKNA2 and increased propensity to develop atherosclerosis | [27, 28] |
(viii) Link between CDKN1 and CDKNB2 polymorphisms and aortic aneurism | [29] |
(ix) ↑ ICAM-1, PAI-1, and IL-1α and ↓ lipid metabolism ability in ECs | [30–33] |
(x) ↑ SASP secretion of annexins and BMPs and ↑Ca2+ in ECs favors calcification onset | [34] |
|