The Regulation of Hyperglycaemia-Induced Exosomal Mir-6499-3p Derived from Vascular Endothelial Cell on Calcification/Senescence of Vascular Smooth Muscle Cells

AUTHORS

Jiayu Zhong, MingHao Yuan, Shuo Hu, En Zhou

ABSTRACT

Diabetes is a prevalent metabolic condition that is closely linked to aging, and its biggest associated risk is vascular related complications. The calcification and aging of blood vessels in diabetes play a significant role in the development of diabetic vascular complications. Growing evidence links exosomal microRNA to the process of diabetic vascular complications. The present study aims to explore the expression, regulatory mechanisms and functions of exosomal miR-6499-3p in the process of diabetic vascular complications. VSMCs could take up exosomes isolated from HUVEC(ECs-exosome) treated with high glucose(HG). These exosomes induced the calcification and senescence of VSMCs through a paracrine mechanism. We then found that HG elevated the expression level of miR-6499-3p both in HUVECs and ECs-exosome. Calcification and senescence of VSMCs can be promoted by ECs-exosomes following overexpression of miR-6499-3p. Furthermore, we demonstrated that the effects of exosomes on the calcification and senescence of VSMCs is mediated by Sclerosin-containing domain SOSTDC1, the potential target of the miR-6499-3p. Our data has shown that a specific role of exosomes from HG-treated HUVEC in regulating the calcification and senescence of VSMCs in a paracrine manner through the miR-6499-3p/SOSTDC1 pathway. Modulation of exosomal miR-6499-3p may provide a novel perspective on the treatment of diabetic vascular complications.

FTO Stabilizes MIS12 to Inhibit Vascular Smooth Muscle Cell Senescence in Atherosclerotic Plaque

AUTHORS

Sun J, Wang M, Jia F, Song J, Ren J, Hu B

ABSTRACT

Purpose: Atherosclerosis is the main cause of atherosclerotic cardiovascular disease (CVD). Here, we aimed to uncover the role and mechanisms of fat mass and obesity-associated genes (FTO) in the regulation of vascular smooth muscle cell (VSMC) senescence in atherosclerotic plaques.

Methods: ApoE−/− mice fed a high-fat diet (HFD) were used to establish an atherosclerotic animal model. Immunohistochemistry, and the staining of hematoxylin-eosin, Oil Red O, Sirius red, and Masson were performed to confirm the role of FTO in atherosclerosis in vivo. Subsequently, FTO expression in primary VSMCs is either upregulated or downregulated. Oxidized low-density lipoprotein (ox-LDL) was used to treat VSMCs, followed by EdU staining, flow cytometry, senescence-associated β-galactosidase (SA-β-gal) staining, immunofluorescence, telomere detection, RT-qPCR, and Western blotting to determine the molecular mechanisms by which FTO inhibits VSMC senescence.

Results: Decreased FTO expression was observed in progressive atherosclerotic plaques of ApoE−/− mice fed with HFD. FTO upregulation inhibits atherosclerotic lesions in mice. FTO inhibits VSMC aging in atherosclerotic plaques by helping VSMC withstand ox-LDL-induced cell cycle arrest and senescence. This process is achieved by stabilizing the MIS12 protein in VSMC through a proteasome-mediated pathway.

Conclusion: FTO inhibits VSMC senescence and subsequently slows the progression of atherosclerotic plaques by stabilizing the MIS12 protein.

The Role of Osteogenic Effect and Vascular Function in Bone Health in Hypertensive Rats: A Study of Anti-hypertensive and Hemorheologic Drugs

AUTHORS

Subhashis Pal, Shivani Sharma, Konica Porwal, Mahesh C. Tiwari, Yasir A. Khan, Saroj Kumar, Navin Kumar & Naibedya Chattopadhyay

ABSTRACT

Vascular dysfunction contributes to the development of osteopenia in hypertensive patients, as decreased blood supply to bones results in tissue damage and dysfunction. The effect of anti-hypertensive medicines on bone mass in hypertensive individuals is inconclusive because of the varied mechanism of their action, and suggests that reducing blood pressure (BP) alone is insufficient to enhance bone mass in hypertension. Pentoxifylline (PTX), a hemorheological drug, improves blood flow by reducing blood viscosity and angiogenesis, also has an osteogenic effect. We hypothesized that improving vascular function is critical to increasing bone mass in hypertension. To test this, we screened various anti-hypertensive drugs for their in vitro osteogenic effect, from which timolol and hydralazine were selected. In adult female spontaneously hypertensive rats (SHRs), timolol and hydralazine did not improve vascular function and bone mass, but PTX improved both. In female SHR animals, PTX restored bone mass, strength and mineralization, up to the level of normotensive control rats. In addition, we observed lower blood vasculature in the femur of adult SHR animals, and PTX restored them. PTX also restored the bone vascular and angiogenesis parameters that had been impaired in OVX SHR compared to sham SHR. This study demonstrates the importance of vascular function in addition to increased bone mass for improving bone health as achieved by PTX without affecting BP, and suggests a promising treatment option for osteoporosis in hypertensive patients, particularly at-risk postmenopausal women.

Vascular Mechanobiology: Homeostasis, Adaptation, and Disease

AUTHORS

Jay D. Humphrey and Martin A. Schwartz

ABSTRACT

Cells of the vascular wall are exquisitely sensitive to changes in their mechanical environment. In healthy vessels, mechanical forces regulate signaling and gene expression to direct the remodeling needed for the vessel wall to maintain optimal function. Major diseases of arteries involve maladaptive remodeling with compromised or lost homeostatic mechanisms. Whereas homeostasis invokes negative feedback loops at multiple scales to mediate mechanobiological stability, disease progression often occurs via positive feedback that generates mechanobiological instabilities. In this review, we focus on the cell biology, wall mechanics, and regulatory pathways associated with arterial health and how changes in these processes lead to disease. We discuss how positive feedback loops arise via biomechanical and biochemical means. We conclude that inflammation plays a central role in overriding homeostatic pathways and suggest future directions for addressing therapeutic needs