Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Background: Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition.

Methods: We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat or protein, respectively.

Results: Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients.

Conclusions: Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions may mediate the association of dietary patterns with risk of CHD.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00051350.

Background: Cept1 is essential for de novo phopholipogenesis and is impacted by diabetes. We previously demonstrated that conditional knockdown of Cept1 in the endothelium leads to reduced tissue recovery. Therefore, we hypothesized that Cept1 overexpression may also be sufficient in promoting postischemic angiogenesis and recovery in the setting of diabetes.

Methods: CEPT1 (choline-ethanolamine phosphotransferase 1) content was evaluated in the peripheral arteries of human patients with peripheral artery disease and with or without diabetes. We also engineered a conditional endothelial cell (EC)-specific Cept1 overexpression mouse (Cept1^fl/fl Cre⁺) in adult C57BL/6J (C57 black 6J) mice and performed unilateral hindlimb ischemia to assess the role of Cept1 in promoting angiogenesis. Murine aortae and ECs were harvested for single-cell RNA sequencing and molecular pathway analysis.

Results: In human arterial intima, CEPT1 was elevated in the setting of peripheral artery disease and diabetes, along with ACOX1 (acyl-coenzyme A oxidase 1), VEGF (vascular endothelial growth factor) R2, p-Akt (phosphorylated Akt), and p-eNOS (phosphorylated endothelial nitric oxide synthase). In mice, single-cell RNA sequencing demonstrated that ECs with Cept1 overexpression were enriched with wound healing, angiogenesis, sprouting, and cell migration pathways. Diabetic Cept1^fl/flCre⁺ mice that underwent hindlimb ischemia demonstrated improved hindlimb perfusion and angiogenesis, and their aortic rings had increased ex vivo capillary sprouting. Cept1 overexpression in ECs significantly increased migration, tubule formation, and proliferation as predicted by single-cell RNA sequencing. Cept1 overexpression in ECs also led to increased expression of Pparα, Acox1, Vegfa, and Vegfr2. Similarly, treatment with siPparα and inhibitors for PPARα (peroxisome proliferator-activated receptor α; GW6471), VEGFR2 (ZM323881), Akt (LY294002), and eNOS (L-NAME [nitro-L-arginine methyl ester]) abrogated CEPT1-induced EC migration.

Conclusions: Cept1 overexpression promotes EC function and postischemic recovery. The impact of CEPT1 on ECs is at least in part dependent on p-Akt/p-eNOS angiogenic signaling and PPARα. Because CEPT1 is elevated in diseased human peripheral arterial tissue, these findings suggest that CEPT1 may be playing an important compensatory role in vascular recovery and reperfusion following ischemic injury in the setting of diabetes.

Background: Lp(a) (lipoprotein[a]) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state.

Methods: Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease undergoing cardiac surgery. These patients were genotyped, and a modified LPA genetic risk score (LPA GRS) determining Lp(a) levels was generated. RNA sequencing and vascular superoxide measurements were performed in internal mammary arteries, and the contribution of NOXs (NADPH oxidases) and uncoupled eNOS (endothelial nitric oxide synthase) was determined. The median follow-up was 5.07 years.

Results: Increased plasma Lp(a) (P=0.03) and LPA GRS (P=0.01) were associated with elevated arterial superoxide in the overall patient population, an effect that was driven by nondiabetics. This effect was primarily due to eNOS uncoupling via reduced vascular BH4 (tetrahydrobiopterin) bioavailability. There was no significant impact of Lp(a) variability on vascular NOX-derived superoxide (P=0.13). RNA sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signaling in high Lp(a) patients although there was no association with systemic biomarkers of inflammation (ie, hsCRP [high-sensitivity C-reactive protein]; P=0.82) or oxidative stress (ie, malondialdehyde; P=0.61). Finally, both LPA GRS (hazard ratio, 3.615 [95% CI, 1.044-12.515]; P=0.043) and high plasma Lp(a) (hazard ratio, 3.286 [95% CI, 1.003-10.767]; P=0.049) were associated with elevated risk for cardiac mortality. This association was vascular superoxide-dependent, implying that redox-sensitive inflammatory signaling may be a link between Lp(a) and cardiovascular risk. All the above associations were independent of plasma ApoB (apolipoprotein-B).

Conclusions: This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis.

The lung endothelium is essential for maintaining normal lung structure and plays a key role in gas exchange, barrier function, angiogenesis, vascular tone, and inflammation regulation. The advent of single-cell RNA sequencing has revealed the unique heterogeneity of pulmonary endothelial cells (ECs) in their function, morphology, and localization. Pulmonary hypertension (PH) is a progressive vascular disorder marked by elevated pulmonary arterial pressure and vascular remodeling. Central to its pathogenesis is EC dysfunction, and emerging evidence highlights EC heterogeneity in driving the complexity of PH. The distinct lung endothelial subpopulations exhibit diverse molecular signatures and functional responses under PH. A complete picture of how these different subpopulations contribute to vascular remodeling of PH is critical to identify novel therapeutic opportunities. This brief review summarizes recent insights into EC dysfunction in PH, focusing on the role of specialized EC subsets and novel therapeutic strategies targeting EC dysfunction. We highlight the integration of cutting-edge technologies in understanding how endothelial heterogeneity shapes the trajectory of PH and opens new avenues for future therapeutic innovations.

Organ transplantation represents a unique environment in which the donor organ undergoes a systemic insult worsened by procurement that is followed by ischemia-reperfusion injury on revascularization. Historically, microvascular thrombosis during sequential injury was considered a cause of organ dysfunction. However, recent data challenge the concept that fibrin deposition in organs drives pathology and instead suggest that the hemostatic system may play an important role in organ recovery. Although fibrin may be protective in the early setting of organ injury, persistent fibrin deposition augments inflammatory leukocyte recruitment that propagates tissue damage. Because the timing of fibrin deposition within the transplanted organ influences both damage and repair, the fibrinolytic system plays an essential role in organ recovery after transplantation. Dysfunctional fibrinolysis is linked to adverse outcomes in many diseases but has received less attention in organ transplantation. This review covers the physiological and pathological role of fibrin formation in liver, kidney, and lung transplantation and discusses how activation of the fibrinolytic system may ultimately modulate outcome.

The plasminogen activation system (PAS) is primarily responsible for the degradation of fibrin clots as well as extracellular matrix remodeling. Many components of the PAS are produced by the liver, and the expression of these proteins is altered during liver disease. Liver is a primary site for the synthesis of proteins in the PAS, including plasminogen, tPA (tissue-type plasminogen activator), and uPA (urokinase-type plasminogen activator), as well as several modulators of plasmin activation. Clinical studies have shown that liver injury profoundly changes levels of PAS components and fibrinolytic activity in plasma. Likewise, there is strong experimental evidence to suggest that components of the PAS play an important role in determining the severity of hepatic injury and, paradoxically, also contribute to repair and regeneration of the injured liver. Here, we review the dynamic connections between the PAS and liver injury/disease, including changes in PAS expression and function accompanying liver disease in patients and mechanism-centered studies in animal models. We focus on established models of acute hepatic injury, chronic liver disease, and repair/regeneration, and review the effect of gain or loss of function of PAS components on the liver. The review seeks to cover not only field-driving discoveries but also spotlights unexplained dichotomies, challenges with interpretation, and the need for further exploration of mechanisms using leading-edge tools. Critical gaps in our understanding of how the PAS contributes to liver pathophysiology, and vice versa, are identified, and future directions are considered.

Pericytes are mural cells that line capillaries throughout the brain, retina, lung, and other organs, where they support capillary homeostasis through direct contact and paracrine crosstalk with capillary endothelium. Despite being described more than a century ago, their contributions to health and vascular diseases remain unclear, largely due to the difficulty of definitive identification. Their inherent plasticity, as well as shared markers and close lineage relationships with other mural cells, results in overlap in identification and underrepresentation in single-cell data sets. Emerging evidence reveals that pericytes play a critical role in the vascular remodeling characteristics of pulmonary hypertension, via mechanisms involving smooth muscle-like phenotypic switching and morphological changes influenced by hypoxia signaling, transforming growth factor-β, cyclic GMP modulation, and disrupted pericyte-endothelial communication. Recent single-cell RNA sequencing enabled the identification of a novel and specific pericyte marker, Higd1b, thereby improving pericyte identification and revealing novel pericyte subtypes. In this review, we summarize historical and recent insights into pericyte morphology and function, their increasingly recognized role in pulmonary hypertension pathobiology, and the potential to unlock novel therapeutic avenues targeting pericytes.

Vascular smooth muscle cells (VSMCs) modulate their phenotype from a quiescent, contractile cell to a dedifferentiated, synthetic fibroproliferative cell in response to injury and cardiovascular risk factors. Senescence is a recognized phenotypically distinct cellular state characterized by cell cycle arrest and activation of the p16 and p53 damage response pathway and expression of the senescence-associated secretory phenotype. Low levels of senescence in healthy arteries contribute to vascular homeostasis by ensuring that only healthy VSMCs compose the artery, but they are not intended to be a persistent cellular component of the artery. However, when discussing VSMC phenotype modulation into foam-like cells, macrophages, mesenchymal cells, fibroblasts, adipocytes, and other VSMC-like cells, senescence is rarely included. This raises an intriguing question: can senescence be recognized as a phenotypic state of VSMCs? As understanding SMC phenotypic switching is crucial for developing therapies that can prevent and treat cardiovascular diseases, so is understanding mechanisms of senescence, and targeting the mechanisms that regulate this modulation could be a promising approach for managing conditions such as atherosclerosis, arterial calcification, and aortic aneurysms. This review aims to summarize recent findings about the molecular mechanisms of VSMC senescence and compare similarities and contrasts with the mechanisms known to regulate VSMC phenotype plasticity. Comparison of transcriptomic databases compelled us to also raise the interesting question: if VSMC can regain their contractile phenotype, can they also be coaxed to exit the senescent state and return to the contractile VSMC phenotype? We posit that senescent VSMCs may not be an end point but rather an intermediate or inflection point in VSMC cell fate decision.