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Angiogenesis and Anti-angiogenesis in Health and Diseases

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 33603

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Special Issue Editor

Dr. Elmina Mammadova-Bach

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Guest Editor

Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
Interests: tumor microenvironment; circulating blood cells; platelets; cancer-associated thrombosis; inflammatory ecosystem of tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolites, nutrients, oxygen and chemical mediators are transported through the blood vessels to maintain and regulate essential physiological functions including organ homeostasis, immune system, body temperature and growth. Vessel formation, angiogenesis is one of the fundamental biological processes involved in embryonic development and also in the growth and metastasis of tumors. Angiogenic switch is an important event during tumor progression where the balance between pro and antiangiogenic factors slope towards a proangiogenic outcome, leading to the transition from avascularized neoplasia to a vascularized tumor. This process of neovascularization was considered a key factor influencing cancer growth. However, several pieces of evidence indicate alternative methods by which blood vessels may influence tumor growth and metastasis, such as vessel cooption, vascular mimicry and intussusceptive angiogenesis. Tumor vessels often appeared abnormal in shape and function, and they are more loosely connected with surrounding cells, such as pericytes and smooth muscle vascular cells, influencing drug delivery. Therefore, preclinical and clinical studies have focused on the role of mural cells, stabilizing the tumor vasculature through various signaling pathways, which influence many hallmarks of cancer, including immune modulation, cell survival and death. However, both defective vasculature and excessive ECM generation and pericyte coverage represent a physical barrier for effective drug delivery, leading to the resistance to the anti-tumor therapies. The efficacy of therapies is also modulated by circulating blood cells, such as monocytes, neutrophils and platelets, which depending on the pathological situation may maintain the integrity of vessels or induce permeability, and creating regenerative, prothrombotic and or proinflammatory environment. Angiogenesis is not limited to cancer; it is also occurring under other pathological conditions, such as diabetic retinopathy, ischemic stroke, myelofibrosis, sickle cell diseases, rheumatoid arthritis, vasculitis and atherogenesis. Current efforts aim to advance research toward the discovery of new molecular targets, gene profiling, resistance mechanisms, and diagnostic and prognostic markers to overcome disease progression by improving the therapeutic options.

Dr. Elmina Mammadova-Bach
Guest Editor

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Keywords

cancer
tumor microenvironment
metastatic niches
angiogenesis
coagulation
blood clotting
vascular integrity
inflammation
thrombo-inflammation
vasculogenesis
lympangiogenesis
diabetic retinopathy
wound healing
immune cells
neutrophils and NETs
cancer and angiogenic dormancy
bone marrow ecosystem
fibrosis
myelofibrosis
synovial inflammation
vasculitis
resistance to the anti-angiogenic and anti-cancer therapies

Published Papers (12 papers)

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13 pages, 2040 KiB

Open AccessArticle

SOD3 Expression in Tumor Stroma Provides the Tumor Vessel Maturity in Oral Squamous Cell Carcinoma

by May Wathone Oo, Hotaka Kawai, Htoo Shwe Eain, Yamin Soe, Kiyofumi Takabatake, Sho Sanou, Qiusheng Shan, Yasunori Inada, Masae Fujii, Yoko Fukuhara, Ziyi Wang, Shintaro Sukegawa, Mitsuaki Ono, Keisuke Nakano and Hitoshi Nagatsuka

Biomedicines 2022, 10(11), 2729; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112729 - 28 Oct 2022

Viewed by 1265

Abstract

Tumor angiogenesis is one of the hallmarks of solid tumor development. The progressive tumor cells produce the angiogenic factors and promote tumor angiogenesis. However, how the tumor stromal cells influence tumor vascularization is still unclear. In the present study, we evaluated the effects of oral squamous cell carcinoma (OSCC) stromal cells on tumor vascularization. The tumor stromal cells were isolated from two OSCC patients with different subtypes: low invasive verrucous squamous carcinoma (VSCC) and highly invasive squamous cell carcinoma (SCC) and co-xenografted with the human OSCC cell line (HSC-2) on nude mice. In comparison, the CD34+ vessels in HSC-2+VSCC were larger than in HSC-2+SCC. Interestingly, the vessels in the HSC-2+VSCC expressed vascular endothelial cadherin (VE-cadherin), indicating well-formed vascularization. Our microarray data revealed that the expression of extracellular superoxide dismutase, SOD3 mRNA is higher in VSCC stromal cells than in SCC stromal cells. Moreover, we observed that SOD3 colocalized with VE-cadherin on endothelial cells of low invasive stroma xenograft. These data suggested that SOD3 expression in stromal cells may potentially regulate tumor vascularization in OSCC. Thus, our study suggests the potential interest in SOD3-related vascular integrity for a better OSCC therapeutic strategy. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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19 pages, 4441 KiB

Open AccessArticle

A Metabolic Signature to Monitor Endothelial Cell Differentiation, Activation, and Vascular Organization

by Filipa Lopes-Coelho, Filipa Martins, Ana Hipólito, Sílvia V. Conde, Sofia A. Pereira, Luís G. Gonçalves and Jacinta Serpa

Biomedicines 2022, 10(9), 2293; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092293 - 15 Sep 2022

Cited by 1 | Viewed by 1366

Abstract

The formation of new blood vessels is an important step in the morphogenesis and organization of tissues and organs; hence, the success of regenerative medicine procedures is highly dependent on angiogenesis control. Despite the biotechnological advances, tissue engineering is still a challenge. Regarding vascular network formation, the regulators are well known, yet the identification of markers is pivotal in order to improve the monitoring of the differentiation and proliferation of endothelial cells, as well as the establishment of a vascular network supporting tissue viability for an efficacious implantation. The metabolic profile accompanies the physiological stages of cells involved in angiogenesis, being a fruitful hub of biomarkers, whose levels can be easily retrieved. Through NMR spectroscopy, we identified branched amino acids, acetate, and formate as central biomarkers of monocyte-to-endothelial-cell differentiation and endothelial cell proliferation. This study reinforces the successful differentiation process of monocytes into endothelial cells, allowing self-to-self transplantation of patient-derived vascular networks, which is an important step in tissue engineering, since monocytes are easily isolated and autologous transplantation reduces the immune rejection events. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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14 pages, 2490 KiB

Open AccessArticle

Veno-Arterial Extracorporeal Membrane Oxygenation (ECMO) Impairs Bradykinin-Induced Relaxation in Neonatal Porcine Coronary Arteries

by Livia Provitera, Giacomo S. Amelio, Matteo Tripodi, Genny Raffaeli, Francesco Macchini, Ilaria Amodeo, Silvia Gulden, Valeria Cortesi, Francesca Manzoni, Gaia Cervellini, Andrea Tomaselli, Gabriele Zuanetti, Caterina Lonati, Michele Battistin, Shady Kamel, Valeria Parente, Valentina Pravatà, Stefania Villa, Eduardo Villamor, Fabio Mosca and Giacomo Cavallaro Show full author list Hide full author list

Biomedicines 2022, 10(9), 2083; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092083 - 25 Aug 2022

Cited by 2 | Viewed by 1780

Abstract

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support for respiratory and cardiovascular failure. However, ECMO induces a systemic inflammatory response syndrome that can lead to various complications, including endothelial dysfunction in the cerebral circulation. We aimed to investigate whether ECMO-associated endothelial dysfunction also affected coronary circulation. Ten-day-old piglets were randomized to undergo either 8 h of veno-arterial ECMO (n = 5) or no treatment (Control, n = 5). Hearts were harvested and coronary arteries were dissected and mounted as 3 mm rings in organ baths for isometric force measurement. Following precontraction with the thromboxane prostanoid (TP) receptor agonist U46619, concentration–response curves to the endothelium-dependent vasodilator bradykinin (BK) and the nitric oxide (NO) donor (endothelium-independent vasodilator) sodium nitroprusside (SNP) were performed. Relaxation to BK was studied in the absence or presence of the NO synthase inhibitor Nω-nitro-L-arginine methyl ester HCl (L-NAME). U46619-induced contraction and SNP-induced relaxation were similar in control and ECMO coronary arteries. However, BK-induced relaxation was significantly impaired in the ECMO group (30.4 ± 2.2% vs. 59.2 ± 2.1%; p < 0.0001). When L-NAME was present, no differences in BK-mediated relaxation were observed between the control and ECMO groups. Taken together, our data suggest that ECMO exposure impairs endothelium-derived NO-mediated coronary relaxation. However, there is a NO-independent component in BK-induced relaxation that remains unaffected by ECMO. In addition, the smooth muscle cell response to exogenous NO is not altered by ECMO exposure. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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19 pages, 2185 KiB

Open AccessArticle

VEGF-A and FGF4 Engineered C2C12 Myoblasts and Angiogenesis in the Chick Chorioallantoic Membrane

by Donna C. Kennedy, Antony M. Wheatley and Karl J. A. McCullagh

Biomedicines 2022, 10(8), 1781; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10081781 - 23 Jul 2022

Cited by 1 | Viewed by 1898

Abstract

Angiogenesis is the formation of new blood vessels from pre-existing vessels. Adequate oxygen transport and waste removal are necessary for tissue homeostasis. Restrictions in blood supply can lead to ischaemia which can contribute to disease pathology. Vascular endothelial growth factor (VEGF) is essential in angiogenesis and myogenesis, making it an ideal candidate for angiogenic and myogenic stimulation in muscle. We established C2C12 mouse myoblast cell lines which stably express elevated levels of (i) human VEGF-A and (ii) dual human FGF4-VEGF-A. Both stably transfected cells secreted increased amounts of human VEGF-A compared to non-transfected cells, with the latter greater than the former. In vitro, conditioned media from engineered cells resulted in a significant increase in endothelial cell proliferation, migration, and tube formation. In vivo, this conditioned media produced a 1.5-fold increase in angiogenesis in the chick chorioallantoic membrane (CAM) assay. Delivery of the engineered myoblasts on Matrigel demonstrated continued biological activity by eliciting an almost 2-fold increase in angiogenic response when applied directly to the CAM assay. These studies qualify the use of genetically modified myoblasts in therapeutic angiogenesis for the treatment of muscle diseases associated with vascular defects. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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15 pages, 3872 KiB

Open AccessArticle

Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization

by Aniket Ramshekar, Colin A. Bretz, Eric Kunz, Thaonhi Cung, Burt T. Richards, Gregory J. Stoddard, Gregory S. Hageman, Brahim Chaqour and M. Elizabeth Hartnett

Biomedicines 2022, 10(7), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071655 - 09 Jul 2022

Viewed by 1506

Abstract

Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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16 pages, 15818 KiB

Open AccessArticle

Matrix Metalloproteinase 10 Contributes to Choroidal Neovascularisation

by Jorge González-Zamora, María Hernandez, Sergio Recalde, Jaione Bezunartea, Ana Montoliu, Valentina Bilbao-Malavé, Josune Orbe, José A. Rodríguez, Sara Llorente-González, Patricia Fernández-Robredo and Alfredo García-Layana

Biomedicines 2022, 10(7), 1557; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071557 - 30 Jun 2022

Cited by 1 | Viewed by 1416

Abstract

Age-related macular degeneration (AMD) is currently the main cause of severe visual loss among older adults in developed countries. The pathophysiology has not been clarified, but oxidative stress is believed to play a major role. Matrix metalloproteinases (MMP) may play a prominent role in several steps of the pathophysiology of AMD, especially in its neovascular form; therefore, there is of great interest in understanding their role in choroidal neovascularisation. This study aimed to elucidate the role of MMP10 in the development of choroidal neovascularisation (CNV). We have demonstrated that MMP10 was expressed by retinal pigment epithelium cells and endothelial cells of the neovascular membrane, in cell culture, mouse and human retina. MMP10 expression and activity increased under oxidative stress conditions in ARPE-19 cells. MMP10^-/- mice developed smaller laser-induced areas of CNV. Furthermore, to exclude a systemic MMP10 imbalance in these patients, plasma MMP10 concentrations were assessed in an age- and sex-matched sample of 52 control patients and 52 patients with neovascular AMD and no significant differences were found between the groups, demonstrating that MMP10 induction is a local phenomenon. Our findings suggest that MMP10 participates in the development of choroidal neovascularisation and promotes MMP10 as a possible new therapeutic target. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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14 pages, 1421 KiB

Open AccessArticle

Proinflammatory Endothelial Phenotype in Very Preterm Infants: A Pilot Study

by Giacomo S. Amelio, Livia Provitera, Genny Raffaeli, Ilaria Amodeo, Silvia Gulden, Valeria Cortesi, Francesca Manzoni, Nicola Pesenti, Matteo Tripodi, Valentina Pravatà, Caterina Lonati, Gaia Cervellini, Fabio Mosca and Giacomo Cavallaro

Biomedicines 2022, 10(5), 1185; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051185 - 20 May 2022

Cited by 2 | Viewed by 1603

Abstract

Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7–10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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13 pages, 3929 KiB

Open AccessArticle

Vascularization of Patient-Derived Tumoroid from Non-Small-Cell Lung Cancer and Its Microenvironment

by Joseph Seitlinger, Anasse Nounsi, Ysia Idoux-Gillet, Eloy Santos Pujol, Hélène Lê, Erwan Grandgirard, Anne Olland, Véronique Lindner, Cécile Zaupa, Jean-Marc Balloul, Eric Quemeneur, Gilbert Massard, Pierre-Emmanuel Falcoz, Guoqiang Hua and Nadia Benkirane-Jessel

Biomedicines 2022, 10(5), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051103 - 10 May 2022

Cited by 5 | Viewed by 2435

Abstract

Patient-derived tumoroid (PDT) has been developed and used for anti-drug screening in the last decade. As compared to other existing drug screening models, a PDT-based in vitro 3D cell culture model could preserve the histological and mutational characteristics of their corresponding tumors and mimic the tumor microenvironment. However, few studies have been carried out to improve the microvascular network connecting the PDT and its surrounding microenvironment, knowing that poor tumor-selective drug transport and delivery is one of the major reasons for both the failure of anti-cancer drug screens and resistance in clinical treatment. In this study, we formed vascularized PDTs in six days using multiple cell types which maintain the histopathological features of the original cancer tissue. Furthermore, our results demonstrated a vascular network connecting PDT and its surrounding microenvironment. This fast and promising PDT model opens new perspectives for personalized medicine: this model could easily be used to test all therapeutic treatments and could be connected with a microfluidic device for more accurate drug screening. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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20 pages, 6051 KiB

Open AccessArticle

Multi-Layered Human Blood Vessels-on-Chip Design Using Double Viscous Finger Patterning

by Elise Delannoy, Géraldine Tellier, Juliette Cholet, Alice M. Leroy, Anthony Treizebré and Fabrice Soncin

Biomedicines 2022, 10(4), 797; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040797 - 29 Mar 2022

Cited by 9 | Viewed by 3880

Abstract

Blood vessel-on-a-chip models aim at reproducing vascular functions. However, very few efficient methods have been designed to address the need for biological replicates in medium- to high-throughput screenings. Here, vessels-on-chip were designed in polydimethylsiloxane-glass chips using the viscous finger patterning technique which was adapted to create channels with various internal diameters inside a collagen solution and to simultaneously seed cells. This method was refined to create blood vessels composed of two concentric, distinct, and closely appositioned layers of human endothelial and perivascular cells arranged around a hollow lumen. These approaches allowed the formation of structurally correct blood vessels-on-chips which were constituted of either only endothelial cells or of both cell types in order to distinguish the vascular barrier reactivity to drugs in the presence or not of perivascular cells. The established vessels showed a tight vascular barrier, as assessed by immunostaining of the adherens junctions, and were reactive to the natural vasopermeant thrombin and to inflammatory cytokines. The presence of perivascular cells markedly increased the tightness of the vascular barrier and lowered its response to thrombin. The design allowed us to simultaneously challenge in real-time several tens of 3D-reconstituted, multicellular blood vessels in a standard multiwell plate format suitable for high-throughput drug screening. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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20 pages, 2452 KiB

Open AccessArticle

Decellularized In Vitro Capillaries for Studies of Metastatic Tendency and Selection of Treatment

by Outi Huttala, Desiree Loreth, Synnöve Staff, Minna Tanner, Harriet Wikman and Timo Ylikomi

Biomedicines 2022, 10(2), 271; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020271 - 26 Jan 2022

Viewed by 2484

Abstract

Vascularization plays an important role in the microenvironment of the tumor. Therefore, it should be a key element to be considered in the development of in vitro cancer assays. In this study, we decellularized in vitro capillaries to remove genetic material and optimized the medium used to increase the robustness and versatility of applications. The growth pattern and drug responses of cancer cell lines and patient-derived primary cells were studied on decellularized capillaries. Interestingly, two distinct growth patterns were seen when cancer cells were grown on decellularized capillaries: “network” and “cluster”. Network formation correlated with the metastatic properties of the cells and cluster formation was observed in non-metastatic cells. Drug responses of patient-derived cells correlated better with clinical findings when cells were cultured on decellularized capillaries compared with those cultured on plastic. Decellularized capillaries provide a novel method for cancer cell culture applications. It bridges the gap between complex 3D culture methods and traditional 2D culture methods by providing the ease and robustness of 2D culture as well as an in vivo-like microenvironment and scaffolding for 3D cultures. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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Review

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22 pages, 941 KiB

Open AccessEditor’s ChoiceReview

Neutrophil Extracellular Traps, Angiogenesis and Cancer

by Remo Poto, Leonardo Cristinziano, Luca Modestino, Amato de Paulis, Gianni Marone, Stefania Loffredo, Maria Rosaria Galdiero and Gilda Varricchi

Biomedicines 2022, 10(2), 431; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020431 - 12 Feb 2022

Cited by 37 | Viewed by 8698

Abstract

Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when exposed to various inflammatory stimuli and in the tumor microenvironment. Neutrophils and their mediators can exert several pro-tumor activities in cancer and promote metastasis through different mechanisms. Angiogenesis plays a pivotal role in inflammation and tumor growth. Activated human neutrophils release several angiogenic factors [vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (ANGPT1), CXCL8, hepatocyte growth factor (HGF), and metalloproteinase 9 (MMP-9)] and form neutrophil extracellular traps (NETs). NETs promote tumor growth and metastasis formation through several mechanisms: they can awake dormant cancer cells, capture circulating tumor cells, coat and shield cancer cells, thus preventing CD8⁺- and natural killer (NK) cell-mediated cytotoxicity. ANGPTs released by endothelial and periendothelial mural cells induce platelet-activating factor (PAF) synthesis and neutrophil adhesion to endothelial cells. NETs can directly exert several proangiogenic activities in human endothelial cells and NETs induced by ANGPTs and PAF increase several aspects of angiogenesis in vitro and in vivo. A better understanding of the pathophysiological functions of NETs in cancer and angiogenesis could be of importance in the early diagnosis, prevention and treatment of tumors. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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26 pages, 4091 KiB

Open AccessSystematic Review

Pathophysiology and Outcomes of Endothelium Function in Coronary Microvascular Diseases: A Systematic Review of Randomized Controlled Trials and Multicenter Study

by Sanjeet Singh Avtaar Singh and Francesco Nappi

Biomedicines 2022, 10(12), 3010; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10123010 - 23 Nov 2022

Cited by 4 | Viewed by 2994

Abstract

Background: Coronary macrovascular disease is a concept that has been well-studied within the literature and has long been the subject of debates surrounding coronary artery bypass grafting (CABG) vs. Percutaneous Coronary Intervention (PCI). ISCHEMIA trial reported no statistical difference in the primary clinical endpoint between initial invasive management and initial conservative management, while in the ORBITA trial PCI did not improve angina frequency score significantly more than placebo, albeit PCI resulted in more patient-reported freedom from angina than placebo. However, these results did not prove the superiority of the PCI against OMT, therefore do not indicate the benefit of PCI vs. the OMT. Please rephrase the sentence. We reviewed the role of different factors responsible for endothelial dysfunction from recent randomized clinical trials (RCTs) and multicentre studies. Methods: A detailed search strategy was performed using a dataset that has previously been published. Data of pooled analysis include research articles (human and animal models), CABG, and PCI randomized controlled trials (RCTs). Details of the search strategy and the methods used for data pooling have been published previously and registered with Open-Source Framework. Results: The roles of nitric oxide (NO), endothelium-derived contracting factors (EDCFs), and vasodilator prostaglandins (e.g., prostacyclin), as well as endothelium-dependent hyperpolarization (EDH) factors, are crucial for the maintenance of vasomotor tone within the coronary vasculature. These homeostatic mechanisms are affected by sheer forces and other several factors that are currently being studied, such as vaping. The role of intracoronary testing is crucial when determining the effects of therapeutic medications with further studies on the horizon. Conclusion: The true impact of coronary microvascular dysfunction (CMD) is perhaps underappreciated, which supports the role of medical therapy in determining outcomes. Ongoing trials are underway to further investigate the role of therapeutic agents in secondary prevention. Full article

(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)

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