The role of the PlGF/Flt-1 signaling pathway in the cardiorenal connection

https://doi.org/10.1016/j.yjmcc.2020.10.001Get rights and content

Highlights

  • Placental growth factor (PlGF) plays roles in inflammatory conditions.

  • Soluble isoform of Flt-1 (sFlt-1) is an intrinsic antagonist for PlGF.

  • PlGF is upregulated and sFlt-1is down regulated in renal failure.

  • Imbalance of PlGF/Flt-1 signaling is involved in cardiorenal connection.

Abstract

Although the concept of the cardiorenal connection is widely accepted, athe underlying molecular mechanism has not been clearly defined. Nevertheless, accumulating evidence indicates that the nervous system and both the humoral and cellular immune systems are all involved. This review article focuses on the roles of the signaling pathway of placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), in the development of the cardiorenal connection. PlGF, a member of the vascular endothelial cell growth factor family, is a specific ligand for Flt-1 and plays roles in the development of atherosclerosis, wound healing after ischemia injury, and angiogenesis through Flt-1 signaling. Flt-1, a tyrosine-kinase type receptor with a single transmembrane domain, has a soluble isoform (sFlt-1) consisting of only extracellular domains, and is an intrinsic antagonist of PlGF. In renal dysfunction, PlGF is upregulated and sFlt-1 is downregulated by oxidative stress or uremic toxins, leading to activation of the PlGF/Flt-1 signaling pathway, which in turn plays a role in the worsening of atherosclerosis and heart failure, both of which are frequently associated with renal dysfunction. Monocyte chemotactic protein-1 (MCP-1) is involved in the process downstream of the Flt-1 signaling pathway. Plasma levels of sFlt-1 correlate with the severity of renal dysfunction in patients with heart failure or myocardial infarction, and are associated with the incidence of cardiovascular events. This is inconsistent with the concept of relative activation of the PlGF/Flt-1 pathway in renal dysfunction. However, the level of circulating sFlt-1 does not always parallel sFlt-1 synthesis, probably because sFlt-1 is stored on cell surfaces through its heparin-binding domains and its quantity is regulated differently in renal dysfunction. This review summarizes a novel concept wherein noninfectious inflammation via PlGF/Flt-1 signaling is involved in the development of renal dysfunction-related cardiovascular complications.

Introduction

Numerous interactions between organs are necessary to maintain health, and their disruption leads to vicious cycles of disease. Although every organ may be involved in disease development, certain organs demonstrate a particularly close relationship with each other. Clinically, heart failure (HF) and renal dysfunction frequently coincide. About 50%–75% of patients with acute HF also have preexisting chronic kidney disease (CKD), which is one of the major risk factors for the development and worsening of HF [[1], [2], [3], [4]]. Thus, there is a very close interaction between the heart and kidneys and is referred to as the cardiorenal connection or cardiorenal syndrome [5,6]. The underlying mechanism responsible for the cardiorenal connection is thought to involve physiological or hemodynamic alterations. However, this mechanism is currently recognized to be highly complex and involves imbalances between the nervous, endocrine, paracrine, inflammatory, and immune systems, induced by cardiac or kidney dysfunction [7].

This review focuses on the means by which the signaling pathway of placental growth factor (PlGF), acting through its receptor, fms-like tyrosine kinase-1 (Flt-1), plays a role in the development of the type of cardiorenal connection in which chronic renal dysfunction precedes cardiac dysfunction.

Section snippets

PlGF

The signaling system of the vascular endothelial cell growth factor (VEGF) family consists of five ligands—VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D—and three tyrosine kinase receptors—VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and VEGFR-3 (Flt-4). The roles of this system in angiogenesis, neuronal regulation, and lymphangiogenesis during fetal development have been well studied, and are also being investigated in the context of tumor development and other ischemic and inflammatory diseases [8,9].

Circulating PlGF in CKD

In patients with CKD, who usually experience worsening of arteriosclerosis and atherosclerosis, plasma PlGF levels are positively correlated with the severity of CKD [16,17]. PlGF was found to be a predictor of all-cause mortality and cardiovascular events, even after adjusting for traditional predictors such as age, CKD stage, and levels of brain natriuretic peptide (BNP). When patients with CKD were divided into four subgroups according to plasma PlGF levels, those in the highest quartile

Worsening of atherosclerosis in 5/6-nephrectomized Apo E−/− mice

Onoue et al. [19] performed an in vivo experiment using 5/6 nephrectomized Apo E−/− mice and found that sFlt-1 mRNA was downregulated in the kidneys and lungs, plasma sFlt-1 level was lower, and plasma PlGF level was higher in the experimental mice than that in the control Apo E−/− mice. Furthermore, the 5/6-nephrectomized mice had significantly larger plaque areas in the thoracoabdominal aorta and aortic root, with massive infiltration of macrophages into the plaques (Fig. 4). These results

Circulating PlGF and sFlt-1 in coronary artery disease

This section reviews the pathological significance of PlGF/Flt-1 signaling in the development of coronary artery disease, a typical atherosclerotic disease. Although few studies have reported that plasma levels of either PlGF or sFlt-1 alone are good markers to determine the severity of coronary artery disease, the ratio of PlGF to sFlt-1 was shown to positively correlate with disease severity and was also considered to be a good marker for cardiac outcomes [24]. In patients with chronic

Circulating PlGF in HF

To understand the pathophysiological significance of PlGF/Flt-1 signaling in the cardiorenal connection, it is important to evaluate the expression profiles of PlGF and sFlt-1 in HF. This is because about 50% of patients with HF have accompanying renal dysfunction with an eGFR <60 mL/min/1.73 m2, and around 20%–30% of patients have an eGFR <30 mL/min/1.73 m2 [[1], [2], [3], [4]]. In patients with chronic HF, plasma PlGF levels increase roughly in parallel with HF severity. Plasma PlGF levels

The role of the imbalance between PlGF and sFlt-1 in the cardiorenal connection

The imbalance between PlGF and sFlt-1 has been well investigated in preeclampsia. In physiological pregnancy, PlGF and sFlt-1 are upregulated to maintain placental function [37,38]. However, in cases of placental hypoxia or impaired perfusion, trophoblasts produce massive amounts of sFlt-1 and suppress PlGF production in the placenta. sFlt-1 is abundantly synthesized in the placenta and circulates systemically in the mother; its plasma levels are more than ten-fold higher than those of PlGF in

Funding sources

This work was supported in part by MEXT KAKENHI Grant Number JP19155855 (Grants-in-aid from the Ministry of Education, Culture, Sports and Science).

Declaration of Competing Interest

Yoshihiko Saito has received the following: research funds from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Actelion Pharmaceuticals Japan, Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma, Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics

Acknowledgement

We thank Kenji Onoue, Masru Matsui, Shiro Uemura, Yukiji Takeda, Hajime Iwama, Ayako Seno, Takaki Matsumoto, and Yasuki Nakada for their help and discussions during the preparation of the manuscript, and Mari Miyagawa for her secretarial work.

References (43)

  • A. Palazzuoli et al.

    Anaemia in heart failure: a common interaction with renal insufficiency called the cardio-renal anaemia syndrome

    Int. J. Clin. Pract.

    (2007)
  • A. Clementi et al.

    Neurohormonal, endocrine, and immune dysregulation and inflammation in cardiorenal syndrome

    Cardiorenal. Med.

    (2019)
  • H. Takahashi et al.

    The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions

    Clin. Sci. (Lond.)

    (2005)
  • M. Shibuya

    Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases

    J. Biochem.

    (2013)
  • M. Dewerchin et al.

    PlGF: a multitasking cytokine with disease-restricted activity

    Cold Spring Harb. Perspect. Med.

    (2012)
  • R. Khurana et al.

    Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation

    Circulation

    (2005)
  • C. Roncal et al.

    Carmeliet, Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable vesions

    Cardiovasc. Res.

    (2010)
  • S. Sela et al.

    A novel human-specific soluble vascular endothelial growth factor receptor 1: cell-type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia

    Circ. Res.

    (2008)
  • S. Sela et al.

    Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparinase

    Circ. Res.

    (2011)
  • V.A. Rosenberg et al.

    Heparin elevates circulating soluble Fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy

    Circulation

    (2011)
  • M. Peiskerová et al.

    Placental growth factor may predict increased left ventricular mass index in patients with mild to moderate chronic kidney disease--a prospective observational study

    BMC Nephrol.

    (2013)
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