Pathophysiological Basis of Vascular Disease

Oxidative stress and smooth muscle cells (SMCs) are major contributors to pulmonary arterial hypertension, atherosclerosis, and systemic hypertension. In this review, the authors discuss how redox balance in SMC by vascular NADPH oxidases, mitochondria bioenergetics, as well as the soluble guanylate cyclase–cyclic guanosine monophosphate–protein kinase G pathway can functionally change SMC from contractile to phenotypically diverse cells and vice versa.

In this study, systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis were investigated. Portal hypertension and signs of a hyperdynamic circulation were demonstrated. NO-independent, COX-2 mediated extrahepatic arterial hyporeactivity, as well as NO-independent alpha-1-adrenergic and endotheline-1 mediated intrahepatic vascular hyperreactivity are demonstrated, likely contributing to the observed portal hypertension in steatosis.

The authors investigated the effect of therapies based on the JAK/STAT regulator SOCS1 to combat diabetes-induced oxidative stress. The SOCS1 gene and peptidomimetic administration prevents renal damage and atherosclerosis in streptozotocin-diabetic mice by reducing oxidative stress and enhancing antioxidant genes. Mechanistically, SOCS1 prevents activation/expression of NADPH oxidase via PI3K and STAT1 inhibition.

Extracellular vesicles (EVs) comprise a wide range of bilayer membrane-enclosed nanovesicles secreted by nearly all cell types and present in all human body fluids. In dilated cardiomyopathy, which is a frequent cause of heart transplantation, unraveling the specific combinations of cargo proteins within the EVs that peripherally circulate in patients hold promising potential for biomarker discovery.

A single high fat meal can induce pathological red blood cell (RBC) remodeling and oxidative stress, in conjunction with elevations in plasma, RBC-bound myeloperoxidase (MPO) and MPO-mediated high-density lipoprotein oxidation. These findings demonstrate that consumption of heavy meals enriched in fat may promote destabilization of vulnerable plaques leading to acute myocardial infarction.

This paper examines whether inhibitor kappa B kinase 2 (IKK2) acts as a myosin light chain kinase (MLCK) or regulates the activity of myosin light chain phosphatase (MLCP), and therefore affects vasoconstriction. The authors found that IKK2 regulates MLCP activity by phosphorylating the MYPT1 subunit. Furthermore, SC-514, an IKK2 inhibitor, induces relaxation of mesenteric arteries. Therefore, IKK2 may be a new pharmacological target for treatment of various vascular diseases.

Hyaluronan (HA) is known to inhibit osteoblast differentiation, but its importance in vascular calcification needed clarification. In this study, the authors identify HA as a novel negative regulator of osteogenic differentiation of vascular smooth muscle cells via bone morphogenetic protein 2 signaling. These results indicate that HA may be a novel potential therapeutic agent for the treatment of vascular calcification.

Currently, therapeutic choices for patients with pulmonary hypertension (PH) are limited. This paper reveals that dipeptidyl peptidase IV inhibition alleviates pulmonary arterial remodeling in PH by decreasing the proliferation and migration of pulmonary arterial smooth muscle cells by regulating PTEN/AKT/MAPK signaling. Therefore, soluble DPP-4 might be a diagnostic or prognostic marker for PH; and DPP-4 inhibitors, potential treatments.

Blood-brain barrier dysfunction and disruption are significant events in central nervous system inflammatory processes. This study shows that TNF-α and VEGF decrease cell-surface cellular prion protein, an adhesion protein, on human brain microvascular endothelial cells, which are a major component of the blood brain barrier. They also show that loss of cellular prion protein results in decreases of the tight junction proteins claudin-5 and occludin and increases permeability of the endothelial layer.

This study characterizes Notch expression and activity, comparing normal blood vessels with atherosclerotic lesions. Smooth muscle cells derived from these sources were used for signaling studies to clarify Notch activity in the diseased state. Proteomic analysis of explanted cells identified differentially expressed proteins in cells from patients with cardiovascular disease.

This study shows that the transcription factor ZBTB46 is expressed in arterial endothelial cells, is regulated by shear stress and cell confluence. ZBTB46 inhibits endothelial cell proliferation through regulation of cell cycle genes, culminating in G0/G1 arrest, and decreased tube formation in an in vitro model of angiogenesis.

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries affecting around 0.5% of the population. The authors analyzed the phenotypic characteristics of chronic and acute murine models of CCM. The acute model harbored higher lesion burden while the chronic model showed more inflammation and lesional iron deposition.

Osteopontin is a critical mediator of post-ischemic neovascularization. Humans express three primary OPN isoforms: OPNa, OPNb, and OPNc. This study demonstrates that OPN isoforms differentially promote functional post-ischemic arteriogenesis by promoting increased macrophage migration and macrophage accumulation and survival. Future studies will determine the molecular mechanisms underlying these divergent effects.

The authors demonstrate that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) induces cardiac hypertrophy and fibrosis via TGF-β1/Smad3 signaling, suggesting that inhibition of gut microbes or generation of TMAO may become a potential target for the prevention and treatment of cardiac hypertrophy.

In this study, the authors found that interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product (SRAGE) on myocardial ischemia/reperfusion (MI/R) injuries in heart, which might be associated with the increasing expression of proteasome β5i. In addition, the increased β5i in cardiomyocytes promoted the p53 degradation which contributed to the anti-apoptosis effects of sRAGE in MI/R injuries.

Human ischemic cardiomyopathy is defined by DNA hypermethylation, methyltransferase EZH2 induction, and transcription factor KLF15 suppression. Together these changes may mediate a gene expression pattern reflecting decreased oxidative phosphorylation and increased cellular remodeling. This study therefore identifies a novel mechanism through which coronary heart disease may be regulated.

This study was designed to investigate the role of polymerase delta interacting protein 2 (Poldip2) in vascular smooth muscle proliferation and neointimal formation. Neointimal formation and proliferating cell nuclear antigen expression were inhibited in Poldip2+/- mice, in part due to induction of the cell cycle inhibitor p21.

Using a novel slingshot 1 phosphatase (SSH1) knock-out mouse model, the authors demonstrate that loss of the actin-binding protein potentiates angiotensin II-induced medial thickening and fibrosis due to altered TGFβ1 signaling, resulting in increased expression of fibronectin and osteopontin.

A poorly developed placental capillary network is associated with early onset fetal growth restriction (FGR) and pre-eclampsia (PE). First trimester placental endothelial cells from pregnancies at increased risk of developing early onset FGR/PE were more sensitive to apoptotic stimuli and this was functionally linked to the synthesis of NO. This may contribute to the poor placental vascular development seen in ongoing pregnancies.

Systemic inflammation generates oxidized high-density lipoprotein (oxHDL) inducing endothelial malfunction mediated by the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). OxHDL interacts with LOX-1 and increases LOX-1 levels to the plasma membrane through the NOX-2/ROS/NF-κB pathway. Oxidative stress is able to induce LOX-1 expression in absence of oxHDL. Also, oxHDL induces TNF-α expression increase, which induces LOX-1 expression.

This paper describes mini-XPerT, a multiplexed screen to simultaneously measure cellular contraction, endothelial barrier function, and cytoskeletal and cell-cell junctional changes. It is the unique combination of these measurements that has enabled the authors to unveil the distinct biophysical mechanisms of barrier defense conferred by Y-27632 and Angpt-1. Mini-XPerT is likely to be applicable across the spectrum of basic and translational science - in mechanistic studies of the endothelium across numerous diseases, and for high-throughput drug discovery.