Single-Cell RNA Sequencing Identifies Response of Renal Lymphatic Endothelial Cells to Acute Kidney Injury.

Significance Statement: The renal lymphatic vasculature and the lymphatic endothelial cells that make up this network play important immunomodulatory roles during inflammation. How lymphatics respond to AKI may affect AKI outcomes. The authors used single-cell RNA sequencing to characterize mouse renal lymphatic endothelial cells in quiescent and cisplatin-injured kidneys.

Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI.

Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase.

Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure.

Aims: Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphangiogenesis in non-ischaemic cardiomyopathy following pressure-overload remains to be determined. Here, we investigated cardiac lymphangiogenesis following transversal aortic constriction (TAC) in C57Bl/6 and Balb/c mice, and in end-stage HF patients.

Cardiac lymphatics: state of the art.

Purpose Of Review: The beneficial role of cardiac lymphatics in health and disease has begun to be recognized, with both preclinical and clinical evidence demonstrating that lymphangiogenesis is activated in cardiovascular diseases. This review aims to summarize our current understanding of the regulation and impact of cardiac lymphatic remodeling during development and in adult life, highlighting emerging concepts regarding distinguishing traits of cardiac lymphatic endothelial cells (LEC).

Recent Findings: Genetic lineage-tracing and clonal analyses have revealed that a proportion of cardiac LECs originate from nonvenous sources.

Lymphatics in the broken heart.

Cardiac lymphatics have emerged as a therapeutic target in cardiovascular diseases to limit myocardial edema and inflammation, notably after myocardial infarction (MI). While most experimental therapeutic approaches have focused on vascular endothelial growth factor C (VEGF-C) delivery, it remains uncertain to what degree the beneficial cardiac effects are related to lymphatic expansion in the heart. In this issue of the JCI, Keller, Lim, et al.

Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week.

The cardiac lymphatic network plays a key role in regulation of myocardial extracellular volume and immune cell homeostasis. In different pathological conditions cardiac lymphatics undergo significant remodeling, with insufficient lymphatic function and/or lymphangiogenesis leading to fluid accumulation and development of edema. Additionally, by modulating the reuptake of tissue-infiltrating immune cells, lymphatics regulate immune responses.

Assessing functional status of cardiac lymphatics: From macroscopic imaging to molecular profiling.

Here we describe various techniques for visualization of the lymphatic vasculature, particularly in the heart. Addressing macro-, microscopic, and molecular levels of lymphatic organization, we give examples of how to explore the roles of specific antigens/markers expressed in lymphatic vessels and their extracellular matrix as structural and functional elements involved in various biological functions of lymphatics. Some obstacles and technical challenges related to lymphatic visualization are also discussed.

Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities.

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development.

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI).

Therapeutic vascular growth in the heart.

Despite tremendous efforts in preclinical research over the last decades, the clinical translation of therapeutic angiogenesis to grow stable and functional blood vessels in patients with ischemic diseases continues to prove challenging. In this mini review, we briefly present the current main approaches applied to improve pro-angiogenic therapies. Specific examples from research on therapeutic cardiac angiogenesis and arteriogenesis will be discussed, and finally some suggestions for future therapeutic developments will be presented.

Cardiac lymphatics in health and disease.

The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in the maintenance of tissue fluid homeostasis, immune cell trafficking, and nutritional lipid uptake and transport, as well as in reverse cholesterol transport. In this Review, we discuss the physiological role of the lymphatic system in the heart in the maintenance of cardiac health and describe alterations in lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We also briefly discuss the role that immune cells might have in the regulation of lymphatic growth (lymphangiogenesis) and function.

[Cardiac lymphatic system].

The lymphatic system is a network of vessels and lymphoid tissues that maintain tissue fluid homeostasis, transport intestinal fat, and regulate immune surveillance. Despite a large body of evidence showing the importance of lymphatic vessels in cardiovascular diseases, the role of cardiac lymphatics has not been extensively investigated. This review highlights the chronology of key discoveries in cardiac lymphatic development and function.

Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

Background: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology.

Role of M2-like macrophage recruitment during angiogenic growth factor therapy.

Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin-alginate microcapsules.

Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome.

Objective: To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).

Methods: Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls.

Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice.

The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs.

Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis.

Objective: Vascular rejection after organ transplantation is characterized by an arterial occlusive lesion, resulting from intimal proliferation occurring in response to arterial wall immune aggression. Our hypothesis is that an early endothelial repair may prevent vascular graft rejection. The aim of the current study was to compare different pharmacologic progenitor cell mobilizing treatments for their protective effects against vascular rejection.

Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

Aims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown.

Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d).

Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure.

Background: Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure.

Methods And Results: First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro.

In vitro and ex vivo evaluation of smart infra-red fluorescent caspase-3 probes for molecular imaging of cardiovascular apoptosis.

Purpose. The aim of this paper is to develop new optical bioprobes for the imaging of apoptosis. Procedure.

Adipose angiogenesis: quantitative methods to study microvessel growth, regression and remodeling in vivo.

Genetic and diet-induced rodent obesity models provide outstanding opportunities to study the role of angiogenesis and vascular remodeling in modulation of adipogenesis and obesity. In this study, we describe methods to quantitatively study adipose angiogenesis and vascular remodeling on the basis of immunohistochemical analyses. Fresh white adipose tissue or brown adipose tissue are prepared for whole mount, cryosectioned and paraffin-embedded samples, followed by staining with specific markers such as platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, CD34, isolectin B4 or alpha-smooth muscle actin.