Axon Guidance-Related Factor FLRT3 Regulates VEGF-Signaling and Endothelial Cell Function

Jauhiainen, Suvi; Laakkonen, Johanna P.; Ketola, Kirsi; Toivanen, Pekka; Nieminen, Tiina; Ninchoji, Takeshi; Levonen, Anna–Liisa; Ylä‐Herttuala, Seppo

doi:10.3389/fphys.2019.00224

Cited by 18 publications

(17 citation statements)

References 49 publications

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“…Much was learned about angiogenesis with the discovery of vascular endothelial growth factor (VEGF). VEGF appears to be intimately involved with wound repair [41] and wound repair requires angiogenesis [42,43]. Others have shown that healthy ECs produce VEGF, which helps control body weight.…”

Section: Discussionmentioning

confidence: 99%

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy

Peterson

Rubinstein

Faroqui

et al. 2019

IJMS

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Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. Results: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. Conclusion: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the “crosstalk” between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.

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Section: Discussionmentioning

confidence: 99%

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy

Peterson

Rubinstein

Faroqui

et al. 2019

IJMS

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“…The fibronectin leucine rich transmembrane protein (FLRT) family may function in cell adhesion and/or receptor signaling [51]. Jauhiainen et al described the role of FLRT3 in the regulation of angiogenesis and vascular patterning via modulation the VEGF-signaling [52]. Moreover, gene-targeting experiments in mice demonstrate demonstrated that Flrt2 is required in the epicardium to promote heart morphogenesis [53].…”

Section: Discussionmentioning

confidence: 99%

Expression Profile of Genes Encoding Proteins Involved in Regulation of Vasculature Development and Heart Muscle Morphogenesis—A Transcriptomic Approach Based on a Porcine Model

Nawrocki

Jopek

Zdun

et al. 2021

IJMS

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Despite significant advances in treatment of acute coronary syndromes (ACS) many subjects still develop heart failure due to significantly reduced ejection fraction. Currently, there are no commonly available treatment strategies that replace the infarcted/dysfunctional myocardium. Therefore, understanding the mechanisms that control the regeneration of the heart muscle is important. The development of new coronary vessels plays a pivotal role in cardiac regeneration. Employing microarray expression assays and RT-qPCR validation expression pattern of genes in long-term primary cultured cells isolated form the right atrial appendage (RAA) and right atrium (RA) was evaluated. After using DAVID software, it indicated the analysis expression profiles of genes involved in ontological groups such as: “angiogenesis”, “blood vessel morphogenesis”, “circulatory system development”, “regulation of vasculature development”, and “vasculature development” associated with the process of creation new blood vessels. The performed transcriptomic comparative analysis between two different compartments of the heart muscle allowed us to indicate the presence of differences in the expression of key transcripts depending on the cell source. Increases in culture intervals significantly increased expression of SFRP2, PRRX1 genes and some other genes involved in inflammatory process, such as: CCL2, IL6, and ROBO1. Moreover, the right atrial appendage gene encoding lysyl oxidase (LOX) showed much higher expression compared to the pre-cultivation state.

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“…Our previous studies showed that mice lacking FLRT2 in vascular endothelial cells exhibit embryonic lethality at mid-gestation with systemic congestion and hypoxia (Tai-Nagara et al, 2017). Notably, FLRT3 is a newly identified member of a family of axon guidance-related factors that participate in VEGFsignaling and regulation of endothelial cell functions (Jauhiainen et al, 2019). We observed that FLRT2 is expressed in the vascular endothelial cells of the hippocampus in adult mice, indicating that FLRT2 may play a key role in maintenance of vascular morphology and function at various stages of development.…”

Section: Discussionmentioning

confidence: 99%

Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury

Shinoda

Ogawa

et al. 2021

Front. Mol. Neurosci.

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Fibronectin and leucine-rich transmembrane (FLRT) proteins are necessary for various developmental processes and in pathological conditions. FLRT2 acts as a homophilic cell adhesion molecule, a heterophilic repulsive ligand of Unc5/Netrin receptors, and a synaptogenic molecule; the last feature is mediated by binding to latrophilins. Although the function of FLRT2 in regulating cortical migration at the late gestation stage has been analyzed, little is known about the expression pattern of FLRT2 during postnatal central nervous system (CNS) development. In this study, we used Flrt2-LacZ knock-in (KI) mice to analyze FLRT2 expression during CNS development. At the early postnatal stage, FLRT2 expression was largely restricted to several regions of the striatum and deep layers of the cerebral cortex. In adulthood, FLRT2 expression was more prominent in the cerebral cortex, hippocampus, piriform cortex (PIR), nucleus of the lateral olfactory tract (NLOT), and ventral medial nucleus (VM) of the thalamus, but lower in the striatum. Notably, in the hippocampus, FLRT2 expression was confined to the CA1 region and partly localized on pre- and postsynapses whereas only few expression was observed in CA3 and dentate gyrus (DG). Finally, we observed temporally limited FLRT2 upregulation in reactive astrocytes around lesion sites 7 days after thoracic spinal cord injury. These dynamic changes in FLRT2 expression may enable multiple FLRT2 functions, including cell adhesion, repulsion, and synapse formation in different regions during CNS development and after spinal cord injury.

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Axon Guidance-Related Factor FLRT3 Regulates VEGF-Signaling and Endothelial Cell Function

Cited by 18 publications

References 49 publications

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy

Expression Profile of Genes Encoding Proteins Involved in Regulation of Vasculature Development and Heart Muscle Morphogenesis—A Transcriptomic Approach Based on a Porcine Model

Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury

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