Development Of Vascular Network Research Articles

Foxp1 suppresses cortical angiogenesis and attenuates HIF-1alpha signaling to promote neural progenitor cell maintenance

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

PIBF1 regulates trophoblast syncytialization and promotes cardiovascular development

Proper placental development in early pregnancy ensures a positive outcome later on. The developmental relationship between the placenta and embryonic organs, such as the heart, is crucial for a normal pregnancy. However, the mechanism through which the placenta influences the development of embryonic organs remains unclear. Trophoblasts fuse to form multinucleated syncytiotrophoblasts (SynT), which primarily make up the placental materno-fetal interface. We discovered that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is vital for trophoblast differentiation and fusion into SynT in humans and mice. PIBF1 facilitates communication between SynT and adjacent vascular cells, promoting vascular network development in the primary placenta. This process affected the early development of the embryonic cardiovascular system in mice. Moreover, in vitro experiments showed that PIBF1 promotes the development of cardiovascular characteristics in heart organoids. Our findings show how SynTs organize the barrier and imply their possible roles in supporting embryogenesis, including cardiovascular development. SynT-derived factors and SynT within the placenta may play critical roles in ensuring proper organogenesis of other organs in the embryo.

A microfluidic platform integrating functional vascularized organoids-on-chip

The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.

GM-CSF Promotes the Development of Dysfunctional Vascular Networks in Moyamoya Disease.

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels. Immune inflammation is associated with the occurrence and development of MMD. However, the mechanisms underlying the formation of the abnormal vascular network remain unclear. Twenty-eight patients with MMD, 26 ischemic stroke patients, and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were higher in MMD patients than in healthy controls (P <0.01), and GM-CSF was mainly from Th1 and Th17 cells in MMD. We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis, inflammation, and chemotaxis. In summary, our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.

Adipocyte Glucocorticoid Receptor Activation With High Glucocorticoid Doses Impairs Healthy Adipose Tissue Expansion by Repressing Angiogenesis.

In Human, glucocorticoids (GC) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GC often lead to adverse side effects including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared to control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of the hypoxiainducible factor HIF-1α and the pro-angiogenic Vascular Endothelial Growth Factor-A expression in GR-deficient adipocytes of AdipoGR-KO mice as compared to control mice, together with an increased adipose vascular network, as assessed by 3D-analysis imaging. GR activation reduced HIF-1α recruitment on Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and post-translational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from Cushing patients, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the down-regulation of the major angiogenic effector VEGFA and inhibiting vascular network development. (LIPOCUSH, NCT01688349).

RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway.

Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by steno-occlusive changes in the circle of Willis and abnormal vascular network development. Ring finger protein 213 (RNF213) has been identified as an important susceptibility gene for Asian patients, but researchers have not completely elucidated whether RNF213 mutations affect the pathogenesis of MMD. Using donor superficial temporal artery (STA) samples, whole-genome sequencing was performed to identify RNF213 mutation types in MMD patients, and histopathology was performed to compare morphological differences between patients with MMD and intracranial aneurysm (IA). The vascular phenotype of RNF213-deficient mice and zebrafish was explored in vivo, and RNF213 knockdown in human brain microvascular endothelial cells (HBMECs) was employed to analyse cell proliferation, migration, and tube formation abilities in vitro. After bioinformatics analysis of both cell and bulk RNA-seq data, potential signalling pathways were measured in RNF213-knockdown or RNF213-knockout endothelial cells (ECs). We found that MMD patients carried pathogenic mutations of RNF213 that were positively associated with MMD histopathology. RNF213 deletion exacerbated pathological angiogenesis in the cortex and retina. Reduced RNF213 expression led to increased EC proliferation, migration, and tube formation. Endothelial knockdown of RNF213 activated the Hippo pathway effector Yes-associated protein (YAP)/tafazzin (TAZ) and promoted the overexpression of the downstream effector VEGFR2. Additionally, inhibition of YAP/TAZ resulted in altered cellular VEGFR2 distribution due to defects in trafficking from the Golgi apparatus to the plasma membrane and reversed RNF213 knockdown-induced angiogenesis. All these key molecules were validated in ECs isolated from RNF213-deficient animals. Our findings may suggest that loss-of-function of RNF213 mediates the pathogenesis of MMD via the Hippo pathway.

From lymphatic endothelial cell migration to formation of tubular lymphatic vascular network.

During development, lymphatic endothelial cell (LEC) progenitors differentiate from venous endothelial cells only in limited regions of the body. Thus, LEC migration and subsequent tube formation are essential processes for the development of tubular lymphatic vascular network throughout the body. In this review, we discuss chemotactic factors, LEC-extracellular matrix interactions and planar cell polarity regulating LEC migration and formation of tubular lymphatic vessels. Insights into molecular mechanisms underlying these processes will help in understanding not only physiological lymphatic vascular development but lymphangiogenesis associated with pathological conditions such as tumors and inflammation.

Biofabricating the vascular tree in engineered bone tissue.

The development of tissue engineering strategies for treatment of large bone defects has become increasingly relevant, given the growing demand for bone substitutes. Native bone is composed of a dense vascular network necessary for the regulation of bone development, regeneration and homeostasis. A major obstacle in fabricating living, clinically relevant-sized bone mimics (1-10 cm3) is the limited supply of nutrients, including oxygen to the core of the construct. Therefore, strategies to support vascularization are pivotal for the development of tissue engineered bone constructs. Creating a functional bone construct integrated with a vascular network, capable of delivering the necessary nutrients for optimal tissue development is imperative for translation into the clinics. The vascular system is composed of a complex network that runs throughout the body in a tree-like hierarchical branching fashion. A significant challenge for tissue engineering approaches lies in mimicking the intricate, multi-scale structures consisting of larger vessels (macro-vessels) which interconnect with multiple sprouting vessels (microvessels) in a closed network. The advent of biofabrication has enabled complex, out of plane channels to be generated and has laid the groundwork for the creation of multi-scale vasculature in recent years. This review highlights the key state-of-the-art achievements for the development of vascular networks of varying scales in the field of biofabrication with a particular focus for its application in developing a functional tissue engineered bone construct. STATEMENT OF SIGNIFICANCE: There is a growing need for bone substitutes to overcome the limited supply of patient-derived bone. Bone tissue engineering aims to overcome this by combining stem cells with scaffolds to restore missing bone. The current bottleneck in upscaling is the lack of an integrated vascular network, required for the delivery of nutrients to cells. 3D bioprinting techniques has enabled the creation of complex hollow structures of varying dimensions that resemble native blood vessels. The convergence of multiple materials, cell types and fabrication approaches, opens the possibility of developing clinically-relevant sized vascularized bone constructs. This review provides an up-to-date insight of the technologies currently available for the generation of complex vascular networks, with a focus on their application in bone tissue engineering.

Moyamoya disease incidentally discovered in head trauma

Moyamoya disease is a chronic cerebral vascular disease of undetermined origin, characterized by stenosis and progressive occlusion of the distal portion of the internal carotid arteries and the proximal portion of the middle and anterior cerebral arteries with resulting, abnormal vascular network development at the base of the skull, realizing a smoke volute appearance or moyamoya. The disease is most common in East Asia. It has two peaks of incidence: around the age of 05 years and during the 4th decade with a female predominance. In children, it leads more frequently to repeated ischemic strokes, while in adults, cerebral hemorrhages are observed. Cerebral MRI and arteriography are the imaging modalities allowing the positive diagnosis of the disease as well as the planning of the management which is based on a revascularization surgery which must be indicated at the optimal period during the follow-up of the disease.

Micro/nano devices for integration with human brain organoids

Brain organoids are powerful experimental models to study fundamental neurodevelopmental processes and the pathology of neurological disorders. Brain organoids can now be generated from human-induced pluripotent stem cells, which pave the way for using them to investigate effective therapies for various neurodegenerative disorders and diseases. However, brain organoids possess complex cellular architecture, various unknown functionalities, and a lack of vascular networks, which have limited their use in biomedicine and clinical research. Micro/nanoscale devices and technologies can help overcome these limitations. This review critically examines recently developed micro/nano devices for integration with brain organoids. The review focuses on devices designed to achieve several key aims: to improve methodologies for in vitro culture; to enable electrophysiological recordings from organoids; to screen drugs for chemotherapy and new treatments; to understand the effects of psychoactive drugs; and to enable development of vascular networks in organoids. Along with the specific device features and their relevance for these applications, we also discuss the current challenges to overcome and future strategies to advance the use of brain organoids in clinical research. The interdisciplinary convergence of brain organoids research with materials science, device engineering, neuroscience, and stem cell biology holds remarkable potential for replicating the human brain in vitro. Micro/nano devices are an important part of realizing this potential that will afford both fundamental insights into the mechanisms underlying brain function and a pathway for developing novel treatments for neurophysiological and neurodegenerative disorders.

WITHDRAWN: Micro- and nanodevices for integration with human brain organoids.

Brain organoids are powerful experimental models to study fundamental neurodevelopmental processes and the pathology of neurological disorders. Brain organoids can now be generated from human-induced pluripotent stem cells, which pave the way for using them to investigate effective therapies for various neurodegenerative disorders and diseases. However, brain organoids possess complex cellular architecture, various unknown functionalities, and a lack of vascular networks, which have limited their use in biomedicine and clinical research. Micro- and nanoscale devices and technologies can help overcome these limitations. This review critically examines recently developed micro- and nanodevices for integration with brain organoids. The review focuses on devices designed to achieve several key aims: to improve methodologies for in vitro culture; to enable electrophysiological recordings from organoids; to screen drugs for chemotherapy and new treatments; to understand the effects of psychoactive drugs; and to enable development of vascular networks in organoids. Along with the specific device features and their relevance for these applications, we also discuss the current challenges to overcome and future strategies to advance the use of brain organoids in clinical research. The interdisciplinary convergence of brain organoids research with materials science, device engineering, neuroscience, and stem cell biology holds remarkable potential for replicating the human brain in vitro . Micro- and nanodevices are an important part of realizing this potential that will afford both fundamental insights into the mechanisms underlying brain function and a pathway for developing novel treatments for neurophysiological and neurodegenerative disorders.

A vasculogenesis model based on flow-induced stresses on endothelial cells

Vascular network formation and sustenance in both normal and pathological froms of angiogenesis has been a focus of research in developmental biology. The assembly and remodeling of vascular structures play major roles in numerous pathologies, including the angiogenesis of tumors. Endothelial morphogenesis is dependent on a number of chemical and mechanical stimuli and cell–cell signaling. To understand the nature of angiogenesis and vasculogenesis, many models have been developed to simulate these phenomena based on the defined responses of endothelial cells to these stimuli. Among the mechanical signals affecting these cells, flow-related stresses, including shear stress, play a major role in migration, elongation, attachment to the matrix and neighboring cells, and eventually the morphogenesis of vascular networks. Here, we proposed a model to describe the cellular responses to shear and tensile stress induced by fluid flow, which can describe some of the morphological behaviors observed in in vitro and in vivo studies. The lattice Boltzmann method was utilized to model the flow, and the cellular Potts model was used to simulate the cellular responses to the flow. This model is based on the hypothesis that endothelial cell binding energy to the matrix is regulated by shear stress and tensile stress acting on the attachment site and is increased by shear stress and decreased by tensile stress. It was demonstrated that these rules can predict the development of vascular networks and the sustenance of lumens and regression in the low flow regions. The results of this study can be further improved to investigate endothelial dysfunctions, such as atherosclerosis, as well as tumor angiogenesis and vascular permeability, which are directly related to the flow rate and endothelial responses to shear stresses.

Anatomy and development of the pectoral fin vascular network in the zebrafish.

The pectoral fins of teleost fish are analogous structures to human forelimbs, and the developmental mechanisms directing their initial growth and patterning are conserved between fish and tetrapods. The forelimb vasculature is crucial for limb function, and it appears to play important roles during development by promoting development of other limb structures, but the steps leading to its formation are poorly understood. In this study, we use high-resolution imaging to document the stepwise assembly of the zebrafish pectoral fin vasculature. We show that fin vascular network formation is a stereotyped, choreographed process that begins with the growth of an initial vascular loop around the pectoral fin. This loop connects to the dorsal aorta to initiate pectoral vascular circulation. Pectoral fin vascular development continues with concurrent formation of three elaborate vascular plexuses, one in the distal fin that develops into the fin-ray vasculature and two near the base of the fin in association with the developing fin musculature. Our findings detail a complex, yet highly choreographed, series of steps involved in the development of a complete, functional, organ-specific vascular network.

Strategies to Induce Blood Vessel Ingrowth into Skin Grafts and Tissue-Engineered Substitutes.

Skin is a multilayer organ consisting of several tissues and appendages residing in a complex niche. Adequate and physiologically regulated vascularization is an absolute requirement for skin homeostasis, regeneration, and wound healing. The lack of vascular networks and ischemia results in delayed wound closure. In addition, vascularization is critical for the prolonged function and survival of skin grafts and tissue-engineered skin substitutes. This study highlights the clinical challenges associated with the limited vascularization in the cutaneous wounds. Then, we highlight the novel approaches for the development of vascular networks in the skin autografts, allografts, and artificial substitutes. Also, the future directions to overcome the existing vascularization complications in skin grafting and synthetic skin substitutes are presented. Statement of Significance Delayed closure of large dermal wounds, such as burn injuries, results from the lack of vascular networks and ischemia. The amount of blood supply in the skin graft is the primary factor determining the quality of the transplanted grafts. The current skin grafts and their fabrication methods lack the appropriate features that contribute to the vascularization and integration of the wound bed and graft and adherence to the skin layers. Therefore, the new generation of skin grafts should consider advanced technologies to induce vascularization and overcome current challenges.

Endoglin Modulates TGFβR2 Induced VEGF and Proinflammatory Cytokine Axis Mediated Angiogenesis in Prolonged DEHP-Exposed Breast Cancer Cells.

Angiogenesis is the process of vascular network development and plays a crucial role in cancer growth, progression, and metastasis. Phthalates are a class of environmental pollutants that have detrimental effects on human health and are reported to increase cancer risk. However, the interplay between phthalate exposure and angiogenesis has not been investigated thoroughly. In this study, we investigated the effect of prolonged di (2-ethylhexyl) phthalate (DEHP) treatment on the angiogenic potential of triple-negative breast cancer. MDA-MB-231 cells were exposed to physiological concentrations of DEHP for more than three months. Prolonged DEHP exposure induced angiogenesis in breast cancer cells. Endoglin (ENG)/CD105 is a membrane glycoprotein and an auxiliary receptor of the TGFβ receptor complex. In endothelial cells, ENG is highly expressed and it is a prerequisite for developmental angiogenesis. A literature review highlights endoglin as a well-known mesenchymal stem cell marker responsible for vascular development and angiogenesis. NGS analysis showed that endoglin overexpression in DEHP-exposed MDA-MB-231 cells correlated with tumor development and growth. An in vivo zebrafish xenograft assay showed that VEGFA induced sprouting of the subintestinal vein (SIV) in embryos injected with DEHP-exposed cells. Endoglin knockdown reduced SIV sprouting and VEGFA expression in zebrafish embryos. An in vitro HUVEC tube formation assay showed that endoglin depletion reversed DEHP-induced VEGF-mediated HUVEC tube formation in coculture. DEHP-induced endoglin activated TGFβ/SMAD3/VEGF and MAPK/p38 signaling in MDA-MB-231 cells. A cytokine angiogenesis antibody array showed induced expression of the inflammatory cytokines IL1α, IL1β, IL6, and IL8, along with GMCSF and VEGF. Endoglin knockdown reversed DEHP-induced activation of the TGFβ/SMAD3/VEGF signaling axis, MAPK/p38 signaling, and cytokine regulation, limiting angiogenesis potential both in vivo and in vitro. Targeting endoglin might serve as a potential alternative treatment to control angiogenesis, leading to metastasis and limiting cancer progression.

Surgical Excision of a Childhood Congenital Vascular Malformation in the Leg: A Rare Inborn Lesion

Congenital vascular malformations are rare anomalies resulting from an inborn error during the vascular network development. They are rare inborn lesions characterized by deficient smooth muscle layer leading to vascular dilatation with impaired functions. Congenital vascular malformations may occur in a spectrum of clinical presentation ranging from ectasia or varicosity to a more complicated lesion that can affect any organ system. Although they are present at birth, they grow proportionally during childhood and adolescence, becoming clinically evident later in life. The symptoms differ depending on location, extension, and size. They may bleed and result in disfigurement, functional impairment, and pain. In this case report, successful surgical treatment of a child with a congenital vascular malformation in his right leg was presented. This case and its detailed intraoperative and radiological images are original as there is no similar example in the available literature.

Precision Medicine for Moyamoya Disease

Moyamoya disease(MMD)is a chronic, occlusive cerebrovascular disease characterized by progressive stenosis at the internal carotid artery terminus and abnormal vascular network formation at the base of the brain. Although its etiology is still unknown, recent genetic analysis identified RNF213 as an important susceptibility gene for MMD. A single nucleotide polymorphism in c.14576G>A(p.R4810K)in RNF213 was identified in 80% of patients with MMD in Japan, and RNF213 mutation was found to be significantly associated with earlier disease onset and more severe disease. More recent studies identified a significant correlation between RNF213 mutation and the intrinsic cerebral hemodynamics, such as local cerebral hyperperfusion after direct revascularization surgery for patients with MMD. These results indicate that RNF213 could be a useful biomarker for the prediction of the clinical course of MMD and/or the outcomes of revascularization surgery. Further investigation is warranted to clarify the exact mechanism by which RNF213 mutation leads to the steno-occlusive changes at the internal carotid artery terminus, development of abnormal vascular networks at the base of the brain, and ultimate cerebrovascular events in patients with MMD. This information could also be helpful in the implementation of precision medicine by providing critical information regarding the molecular target candidates in the management of MMD.

Hypoxia: Role of SIRT1 and the protective effect of resveratrol in ovarian function.

BackgroundOvarian function is closely related to the degree of vascular network development surrounding the ovary. Maternal aging‐related construction defects in this vascular network can cause ovarian hypoxia, which impedes oocyte nutrient supply, leading to physiological changes in the ovaries and oocytes. The anti‐aging gene Sirtuin 1 (SIRT1) senses and adapts to ambient stress and is associated with hypoxic environments and mitochondrial biogenesis.MethodsThe present study is a literature review focusing on investigations involving the changes in SIRT1 and mitochondrial expression during hypoxia and the cytoprotective effects of the SIRT1 activator, resveratrol.Main findingsHypoxia suppresses SIRT1 and mitochondrial expression. Resveratrol can reverse the hypoxia‐induced decrease in mitochondrial and SIRT1 activity. Resveratrol suppresses the production of hypoxia‐inducible factor‐1α and vascular endothelial growth factor proteins.ConclusionResveratrol exhibits protective activity against hypoxic stress and may prevent hypoxia‐ or aging‐related mitochondrial dysfunction. Resveratrol treatment may be a potential option for infertility therapy.

SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of interferon-deficient tumor-associated neutrophils.

Angiogenesis plays an important role during tumor growth and metastasis. We could previously show that Type I interferon (IFN)-deficient tumor-associated neutrophils (TANs) show strong pro-angiogenic activity, and stimulate tumor angiogenesis and growth. However, the exact mechanism responsible for their pro-angiogenic shift is not clear. Here, we set out to delineate the molecular mechanism and factors regulating pro-angiogenic properties of neutrophils in the context of Type I IFN availability. We demonstrate that neutrophils from IFN-deficient (Ifnar1-/- ) mice efficiently release pro-angiogenic factors, such as VEGF, MMP9 or BV8, and thus significantly support the vascular normalization of tumors by increasing the maturation of perivascular cells. Mechanistically, we could show here that the expression of pro-angiogenic factors in neutrophils is controlled by the transcription factor forkhead box protein O3a (FOXO3a), which activity depends on its post-translational modifications, such as deacetylation or phosphorylation. In TANs isolated from Ifnar1-/- mice, we observe significantly elevated SIRT1, resulting in SIRT1-mediated deacetylation of FOXO3a, its nuclear retention and activation. Activated FOXO3a supports in turn the transcription of pro-angiogenic genes in TANs. In the absence of SIRT1, or after its inhibition in neutrophils, elevated kinase MEK/ERK and PI3K/AKT activity is observed, leading to FOXO3a phosphorylation, cytoplasmic transfer and inactivation. In summary, we have found that FOXO3a is a key transcription factor controlling the angiogenic switch of neutrophils. Post-translational FOXO3a modifications regulate its transcriptional activity and, as a result, the expression of pro-angiogenic factors supporting development of vascular network in growing tumors. Therefore, targeting FOXO3a activity could provide a novel strategy of antiangiogenic targeted therapy for cancer.

The development of tumour vascular networks

The growth of solid tumours relies on an ever-increasing supply of oxygen and nutrients that are delivered via vascular networks. Tumour vasculature includes endothelial cell lined angiogenesis and the less common cancer cell lined vasculogenic mimicry (VM). To study and compare the development of vascular networks formed during angiogenesis and VM (represented here by breast cancer and pancreatic cancer cell lines) a number of in vitro assays were utilised. From live cell imaging, we performed a large-scale automated extraction of network parameters and identified properties not previously reported. We show that for both angiogenesis and VM, the characteristic network path length reduces over time; however, only endothelial cells increase network clustering coefficients thus maintaining small-world network properties as they develop. When compared to angiogenesis, the VM network efficiency is improved by decreasing the number of edges and vertices, and also by increasing edge length. Furthermore, our results demonstrate that angiogenic and VM networks appear to display similar properties to road traffic networks and are also subject to the well-known Braess paradox. This quantitative measurement framework opens up new avenues to potentially evaluate the impact of anti-cancer drugs and anti-vascular therapies.