Journal of Vascular Research最新文献

Objective: Follicle-stimulating hormone (FSH) level changes may be another reason for increasing the risk of cardiovascular disease. In this study, we aimed to investigate the role of FSH in atherosclerosis and its underlying mechanism.

Methods: ApoE-/- mice were divided into 4 groups, namely, the sham group, bilaterally orchidectomized group, FSH group, and testosterone-only group. Blood lipid and hormone levels were tested, aorta Oil Red O staining; the levels of NF-κB, Akt, eNOS, and FSH receptors in the aorta were measured by Western blotting. Expression of VCAM-1 was detected via Western blotting and immunohistochemical staining. Human umbilical vein endothelial cells (HUVECs) were used to induce endothelial injury model by adding FSH, and the levels of NF-κB, Akt, eNOS, and FSHR were tested in HUVECs.

Results: FSH treatment exacerbated atherosclerotic lesions in ApoE-/- mice. Moreover, FSH could promote the expression of VCAM-1 protein in HUVECs, and this effect was possibly mediated by the activation of NF-κB, while NF-κB activation was further enhanced by the activation of the PI3K/Akt/eNOS pathway. FSH failed to activate Akt and NF-κB in the presence of the PI3K inhibitor LY294002 in HUVECs.

Conclusion: FSH promoted the development of atherosclerosis by increasing VCAM-1 protein expression via activating PI3K/Akt/NF-κB pathway.

Tumors induce angiogenesis to acquire oxygen and nutrition from their adjacent microenvironment. Tumor angiogenesis has been believed to be induced primarily by the secretion of vascular endothelial growth factor-A (VEGF-A) from various tumors. VEGF-A binds to VEGF receptor 2 (VEGFR2), resulting in subsequent activation of cellular substances regulating cell proliferation, survival, and angiogenesis. Antiangiogenic therapies targeting the VEGF-A/VEGFR2 axis, including bevacizumab and ramucirumab, humanized monoclonal antibodies against VEGF-A and VEGFR2, respectively, have been proposed as a promising strategy aimed at preventing tumor growth, invasion, and metastasis. Phase III clinical trials using bevacizumab and ramucirumab have shown that not all tumor patients benefit from such antiangiogenic agents, and that some patients who initially benefit subsequently become less responsive to these antibodies, suggesting the possible existence of VEGF-independent angiogenic factors. In this review, we focus on VEGF-independent and VEGFR2-dependent tumor angiogenesis, as well as VEGFR2-independent tumor angiogenesis. Additionally, we discuss VEGF-independent angiogenic factors which have been reported in previous studies. Various molecular targeting drugs are currently being evaluated as potential antitumor therapies. We expect that precision medicine will permit the development of innovative antiangiogenic therapies targeting individual angiogenic factors selected on the basis of the genetic screening of tumors.

Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This review focuses on the emerging role which ADAMTS-4 might play in vascular pathology, which has implications for atherosclerosis and vessel wall abnormalities, as well as for the resulting diseases, such as cardiovascular and cerebrovascular disease, aortic aneurysms, and dissections. Major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels. Good examples are versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy, which is why this metzincin protease was implicated in the pathophysiology of vascular diseases with an atherosclerotic background. Despite emerging evidence, it is important not to exaggerate the role of ADAMTS-4 as it is likely only a small piece of the complex atherosclerosis puzzle and one that could be functionally redundant due to its high structural similarity to other ADAMTS family members. The therapeutic potential of inhibiting ADAMTS-4 to halt the progression of vascular disease after initialization of treatment is unlikely. However, it is not excluded that it might find a purpose as a biomarker of vascular disease, possibly as an indicator in a larger cytokine panel.

Adipose-derived stromal vascular fraction (SVF) has emerged as a potential regenerative therapy, but few studies utilize SVF in a setting of advanced age. Additionally, the specific cell population in SVF providing therapeutic benefit is unknown. We hypothesized that aging would alter the composition of cell populations present in SVF and its ability to promote angiogenesis following injury, a mechanism that is T cell-mediated. SVF isolated from young and old Fischer 344 rats was examined with flow cytometry for cell composition. Mesenteric windows from old rats were isolated following exteriorization-induced (EI) hypoxic injury and intravenous injection of one of four cell therapies: (1) SVF from young or (2) old donors, (3) SVF from old donors depleted of or (4) enriched for T cells. Advancing age increased the SVF T-cell population but reduced revascularization following injury. Both young and aged SVF incorporated throughout the host mesenteric microvessels, but only young SVF significantly increased vascular area following EI. This study highlights the effect of donor age on SVF angiogenic efficacy and demonstrates how the ex vivo mesenteric-window model can be used in conjunction with SVF therapy to investigate its contribution to angiogenesis.

Introduction: We previously identified Notch2 in smooth muscle cells (SMC) in human atherosclerosis and found that signaling via Notch2 suppressed human SMC proliferation. Thus, we tested whether loss of Notch2 in SMC would alter atherosclerotic plaque progression using a mouse model.

Methods: Atherogenesis was examined at the brachiocephalic artery and aortic root in a vascular SMC null (inducible smooth muscle myosin heavy chain Cre) Notch2 strain on the ApoE-/- background. We measured plaque morphology and size, as well as lipid, inflammation, and smooth muscle actin content after Western diet.

Results: We generated an inducible SMC Notch2 null on the ApoE-/- background. We observed ∼90% recombination efficiency with no detectable Notch2 in the SMC. Loss of SMC Notch2 did not significantly change plaque size, lipid content, necrotic core, or medial area. However, loss of SMC Notch2 reduced the contractile SMC in brachiocephalic artery lesions and increased inflammatory content in aortic root lesions after 6 weeks of Western diet. These changes were not present with loss of SMC Notch2 after 14 weeks of Western diet.

Conclusions: Our data show that loss of SMC Notch2 does not significantly reduce atherosclerotic lesion formation, although in early stages of plaque formation there are changes in SMC and inflammation.

Pulmonary arterial hypertension (PAH) is a chronic progressive disease with significant morbidity and mortality. The disease is characterized by vascular remodeling that includes increased muscularization of distal blood vessels and vessel stiffening associated with changes in extracellular matrix deposition. In humans, chronic hypoxia causes PAH, and hypoxia-induced rodent models of PAH have been used for years to study the disease. With the development of single-cell RNA sequencing technology, it is now possible to examine hypoxia-dependent transcriptional changes in vivo at a cell-specific level. In this study, we used single-cell RNA sequencing to compare lungs from wild-type (Wt) mice exposed to hypoxia for 28 days to normoxia-treated control mice. We additionally examined mice deficient for Notch3, a smooth muscle-enriched gene linked to PAH. Data analysis revealed that hypoxia promoted cell number changes in immune and endothelial cell types in the lung, activated the innate immunity pathway, and resulted in specific changes in gene expression in vascular cells. Surprisingly, we found limited differences in lungs from mice deficient for Notch3 compared to Wt controls. These findings provide novel insight into the effects of chronic hypoxia exposure on gene expression and cell phenotypes in vivo and identify unique changes to cells of the vasculature.

Introduction: Nocturnal systolic blood pressure (SBP) dipping is independently related to cardiovascular disease risk, but it is unclear if vascular insulin sensitivity associates with SBP dipping in patients with metabolic syndrome (MetS).

Methods: Eighteen adults with MetS (ATP III criteria 3.3 ± 0.6; 53.2 ± 6.5 years; body mass index 35.8 ± 4.5 kg/m2) were categorized as "dippers" (≥10% change in SBP; n = 4 F/3 M) or "non-dippers" (<10%; n = 9 F/2 M). Twenty-four-hour ambulatory blood pressure was recorded to assess SBP dipping. A euglycemic-hyperinsulinemic clamp (40 mU/m2/min, 90 mg/dL) with ultrasound (flow mediated dilation) was performed to test vascular insulin sensitivity. A graded, incremental exercise test was conducted to estimate sympathetic activity. Heart rate (HR) recovery after exercise was then used to determine parasympathetic activity. Metabolic panels and body composition (DXA) were also tested.

Results: Dippers had greater drops in SBP (16.63 ± 5.2 vs. 1.83 ± 5.6%, p < 0.01) and experienced an attenuated rise in both SBPslope (4.7 ± 2.3 vs. 7.2 ± 2.5 mm Hg/min, p = 0.05) and HRslope to the incremental exercise test compared to non-dippers (6.5 ± 0.9 vs. 8.2 ± 1.7 bpm/min, p = 0.03). SBP dipping correlated with higher insulin-stimulated flow-mediated dilation (r = 0.52, p = 0.03), although the relationship was no longer significant after covarying for HRslope (r = 0.42, p = 0.09).

Conclusion: Attenuated rises in blood pressure and HR to exercise appear to play a larger role than vascular insulin sensitivity in SBP dipping in adults with MetS.

Blood vessels are subjected to mechanical loads of pressure and flow, inducing smooth muscle circumferential and endothelial shear stresses. The perception and response of vascular tissue and living cells to these stresses and the microenvironment they are exposed to are critical to their function and survival. These mechanical stimuli not only cause morphological changes in cells and vessel walls but also can interfere with biochemical homeostasis, leading to vascular remodeling and dysfunction. However, the mechanisms underlying how these stimuli affect tissue and cellular function, including mechanical stimulation-induced biochemical signaling and mechanical transduction that relies on cytoskeletal integrity, are unclear. This review focuses on signaling pathways that regulate multiple biochemical processes in vascular mesangial smooth muscle cells in response to circumferential stress and are involved in mechanosensitive regulatory molecules in response to mechanotransduction, including ion channels, membrane receptors, integrins, cytoskeletal proteins, nuclear structures, and cascades. Mechanoactivation of these signaling pathways is closely associated with vascular remodeling in physiological or pathophysiological states.