VASH1
Tubulinyl-Tyr carboxypeptidase 1 (EC 3.4.17.17) (Tubulin carboxypeptidase 1) (Tyrosine carboxypeptidase 1) (TTCP 1) (Vasohibin-1) [KIAA1036] [VASH]
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The structural and functional integrity of endothelium is essential for the maintenance of vascular health. Vasohibin-1 (VASH1), originally isolated as an endothelium-derived angiogenesis inhibitor, has another function to promote stress tolerance of endothelial cells (ECs), and these functions are critical for the maintenance of vascular homeostasis preventing both pathological angiogenesis and stress-induced vascular diseases. The expression of VASH1 is downregulated during replicative senescence of ECs by the alteration of microRNA expression, and this age-associated downregulation of VASH1 might be a risk of deterioration of vascular homeostasis and age-related vascular diseases. Contrary to this expectation, the lack of Vash1 gene in mice exhibited healthy longevity. Thus, VASH1 has double-face for the maintenance of vascular homeostasis and healthy longevity. This feature of VASH1 and its mechanism will be described in this mini review.
MeSH Terms
- Cell Cycle Proteins
- Endothelium, Vascular
- Homeostasis
- Humans
- Longevity
- Neovascularization, Physiologic
Keywords
- , Vascular stress tolerance
- Angiogenesis inhibition
- Healthy longevity
- Vasohibin-1
Vasohibin-1 (VASH1) is an angiogenesis-inhibiting factor synthesized by endothelial cells (ECs) and it also functions to increase stress tolerance of ECs, which function is critical for the maintenance of vascular integrity. Here, we examined whether the expression of VASH1 would be affected by aging. We passaged human umbilical vein endothelial cells (HUVECs) and observed that VASH1 was downregulated in old HUVECs. This decrease in VASH1 expression with aging was confirmed in mice. To explore the mechanism of this downregulation, we compared the expression of microRNAs between old and young HUVECs by performing microarray analysis. Among the top 20 microRNAs that were expressed at a higher level in old HUVECs, the third highest microRNA, namely miR-22-3p, had its binding site on the 3' UTR of VASH1 mRNA. Experiments with microRNA mimic and anti-miR revealed that miR-22-3p was involved at least in part in the downregulation of VASH1 in ECs during replicative senescence. We then clarified the significance of this defective expression of VASH1 in the vasculature. When a cuff was placed around the femoral arteries of wild-type mice and VASH1-null mice, neointimal formation was augmented in the VASH1-null mice accompanied by an increase in adventitial angiogenesis, macrophage accumulation in the adventitia, and medial/neointimal proliferating cells. These results indicate that in replicative senescence, the downregulation of VASH1 expression in ECs was caused, at least in part, by the alteration of microRNA expression. Such downregulation of VASH1 might be involved in the acceleration of age-associated vascular diseases.
MeSH Terms
- Animals
- Apolipoproteins E
- Atherosclerosis
- Cell Cycle Proteins
- Cellular Senescence
- Down-Regulation
- Endothelial Cells
- Human Umbilical Vein Endothelial Cells
- Humans
- Mice, Inbred C57BL
- MicroRNAs
- Neointima
Keywords
- aging
- angiogenesis
- endothelial cell
- replicative senescence