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16 pages, 2139 KiB

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Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway

by Hannah Murray, Beiying Qiu, Sze Yuan Ho and Xiaomeng Wang

Int. J. Mol. Sci. 2021, 22(17), 9580; https://doi.org/10.3390/ijms22179580 - 3 Sep 2021

Cited by 9 | Viewed by 2416

Abstract

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 [...] Read more.

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. In addition to its role in activating the AP, CFB has been implicated in pathological ocular neovascularization, a common feature of several blinding eye diseases, however, with somewhat conflicting results. The focus of this study was to investigate the direct impact of CFB on ocular neovascularization in a tightly controlled environment. Using mouse models of laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), our study demonstrated an increase in CFB expression during pathological angiogenesis. Results from several in vitro and ex vivo functionality assays indicated a promoting effect of CFB in angiogenesis. Mechanistically, CFB exerts this pro-angiogenic effect by mediating the vascular endothelial growth factor (VEGF) signaling pathway. In summary, we demonstrate compelling evidence for the role of CFB in driving ocular angiogenesis in a VEGF-dependent manner. This work provides a framework for a more in-depth exploration of CFB-mediated effects in ocular angiogenesis in the future. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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9 pages, 924 KiB

Open AccessArticle

MAPKs Are Highly Abundant but Do Not Contribute to α₁-Adrenergic Contraction of Rat Saphenous Arteries in the Early Postnatal Period

by Dina K. Gaynullina, Tatiana V. Kudryashova, Alexander V. Vorotnikov, Rudolf Schubert and Olga S. Tarasova

Int. J. Mol. Sci. 2021, 22(11), 6037; https://doi.org/10.3390/ijms22116037 - 3 Jun 2021

Cited by 2 | Viewed by 1966

Abstract

Previously, the abundance of p42/44 and p38 MAPK proteins had been shown to be higher in arteries of 1- to 2-week-old compared to 2- to 3-month-old rats. However, the role of MAPKs in vascular tone regulation in early ontogenesis remains largely unexplored. We [...] Read more.

Previously, the abundance of p42/44 and p38 MAPK proteins had been shown to be higher in arteries of 1- to 2-week-old compared to 2- to 3-month-old rats. However, the role of MAPKs in vascular tone regulation in early ontogenesis remains largely unexplored. We tested the hypothesis that the contribution of p42/44 and p38 MAPKs to the contraction of peripheral arteries is higher in the early postnatal period compared to adulthood. Saphenous arteries of 1- to 2-week-old and 2- to 3-month-old rats were studied using wire myography and western blotting. The α₁-adrenoceptor agonist methoxamine did not increase the phosphorylation level of p38 MAPK in either 1- to 2-week-old or 2- to 3-month-old rats. Accordingly, inhibition of p38 MAPK did not affect arterial contraction to methoxamine in either age group. Methoxamine increased the phosphorylation level of p42/44 MAPKs in arteries of 2- to 3-month-old and of p44 MAPK in 1- to 2-week-old rats. Inhibition of p42/44 MAPKs reduced methoxamine-induced contractions in arteries of 2- to 3-month-old, but not 1- to 2-week-old rats. Thus, despite a high abundance in arterial tissue, p38 and p42/44 MAPKs do not regulate contraction of the saphenous artery in the early postnatal period. However, p42/44 MAPK activity contributes to arterial contractions in adult rats. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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11 pages, 1707 KiB

Open AccessArticle

Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

by Hyeon Young Park, Mi-Jin Kim, Seunghyeong Lee, Jonghwa Jin, Sungwoo Lee, Jung-Guk Kim, Yeon-Kyung Choi and Keun-Gyu Park

Int. J. Mol. Sci. 2021, 22(11), 5602; https://doi.org/10.3390/ijms22115602 - 25 May 2021

Cited by 12 | Viewed by 3190

Abstract

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new [...] Read more.

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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21 pages, 8240 KiB

Open AccessArticle

MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation

by Yu-Chung Shih, Po-Yuan Chen, Tai-Ming Ko, Po-Hsun Huang, Hsu Ma and Der-Cherng Tarng

Int. J. Mol. Sci. 2021, 22(11), 5448; https://doi.org/10.3390/ijms22115448 - 21 May 2021

Cited by 14 | Viewed by 3561

Abstract

Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on [...] Read more.

Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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19 pages, 5429 KiB

Open AccessArticle

Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension

by Baptiste Gouyou, Katja Grün, Anne Kerschenmeyer, Alessandra Villa, Mattia Matasci, Andrea Schrepper, Alexander Pfeil, Laura Bäz, Christian Jung, P. Christian Schulze, Dario Neri and Marcus Franz

Int. J. Mol. Sci. 2021, 22(7), 3460; https://doi.org/10.3390/ijms22073460 - 27 Mar 2021

Cited by 10 | Viewed by 2837

Abstract

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. [...] Read more.

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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12 pages, 5192 KiB

Open AccessArticle

Vasa Vasorum Lumen Narrowing in Brain Vascular Hyalinosis in Systemic Hypertension Patients Who Died of Ischemic Stroke

by Sergiy G. Gychka, Nataliia V. Shults, Sofia I. Nikolaienko, Lucia Marcocci, Nurefsan E. Sariipek, Vladyslava Rybka, Tatiana A. Malysheva, Vyacheslav A. Dibrova, Yuichiro J. Suzuki and Alexander S. Gavrish

Int. J. Mol. Sci. 2020, 21(24), 9611; https://doi.org/10.3390/ijms21249611 - 17 Dec 2020

Cited by 2 | Viewed by 2859

Abstract

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to vascular lumen narrowing and stroke, [...] Read more.

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of the vasa vasorum and oxidative stress. Transmission electron microscopy revealed endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. The siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich syndrome protein (a regulator of actin polymerization). Spontaneously hypertensive stroke-prone rats also exhibited lesions indicative of brain vascular hyalinosis, the endothelial cell protrusion into the lumen of the vasa vasorum, and endocytosis in vasa vasorum endothelial cells. We propose that endocytosis-dependent endothelial cell bulge protrusion narrows the vasa vasorum, resulting in ischemic oxidative damage to cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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19 pages, 1261 KiB

Open AccessArticle

Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis

by Miquel Navas-Madroñal, Esmeralda Castelblanco, Mercedes Camacho, Marta Consegal, Anna Ramirez-Morros, Maria Rosa Sarrias, Paulina Perez, Nuria Alonso, María Galán and Dídac Mauricio

Int. J. Mol. Sci. 2020, 21(19), 7360; https://doi.org/10.3390/ijms21197360 - 5 Oct 2020

Cited by 16 | Viewed by 3579

Abstract

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. [...] Read more.

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1′-dioctadecyl-3,3,3′,3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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Review

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20 pages, 867 KiB

Open AccessReview

Cellular Crosstalk between Endothelial and Smooth Muscle Cells in Vascular Wall Remodeling

by Nerea Méndez-Barbero, Carmen Gutiérrez-Muñoz and Luis Miguel Blanco-Colio

Int. J. Mol. Sci. 2021, 22(14), 7284; https://doi.org/10.3390/ijms22147284 - 6 Jul 2021

Cited by 95 | Viewed by 10381

Abstract

Pathological vascular wall remodeling refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease (CVD). Vessel wall are composed of two major primary cells types, endothelial cells (EC) and vascular [...] Read more.

Pathological vascular wall remodeling refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease (CVD). Vessel wall are composed of two major primary cells types, endothelial cells (EC) and vascular smooth muscle cells (VSMCs). The physiological communications between these two cell types (EC–VSMCs) are crucial in the development of the vasculature and in the homeostasis of mature vessels. Moreover, aberrant EC–VSMCs communication has been associated to the promotor of various disease states including vascular wall remodeling. Paracrine regulations by bioactive molecules, communication via direct contact (junctions) or information transfer via extracellular vesicles or extracellular matrix are main crosstalk mechanisms. Identification of the nature of this EC–VSMCs crosstalk may offer strategies to develop new insights for prevention and treatment of disease that curse with vascular remodeling. Here, we will review the molecular mechanisms underlying the interplay between EC and VSMCs. Additionally, we highlight the potential applicable methodologies of the co-culture systems to identify cellular and molecular mechanisms involved in pathological vascular wall remodeling, opening questions about the future research directions. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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12 pages, 653 KiB

Open AccessReview

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels

by Anastasia A. Shvetsova, Dina K. Gaynullina, Olga S. Tarasova and Rudolf Schubert

Int. J. Mol. Sci. 2021, 22(11), 5413; https://doi.org/10.3390/ijms22115413 - 21 May 2021

Cited by 9 | Viewed by 2557

Abstract

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote [...] Read more.

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from K_ir2, K_v1, K_v7 and TASK-1 channels to BK_Ca channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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18 pages, 2309 KiB

Open AccessReview

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

by Inés Roger, Javier Milara, Paula Montero and Julio Cortijo

Int. J. Mol. Sci. 2021, 22(9), 4980; https://doi.org/10.3390/ijms22094980 - 7 May 2021

Cited by 36 | Viewed by 6027

Abstract

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery [...] Read more.

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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17 pages, 1297 KiB

Open AccessReview

Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway

by Ho-Wei Hsu, Ting-Yi Lin, Yi-Ching Liu, Jwu-Lai Yeh and Jong-Hau Hsu

Int. J. Mol. Sci. 2021, 22(6), 3238; https://doi.org/10.3390/ijms22063238 - 22 Mar 2021

Cited by 11 | Viewed by 2817

Abstract

The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a [...] Read more.

The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling)

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