Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

Micro/nano-plastics impacts in cardiovascular systems across species.

The widespread presence of microplastics and nanoplastics (MPs/NPs) in the environment has become a critical public health issue due to their potential to infiltrate and affect various biological systems. Our review is crucial as it consolidates current data and provides a comprehensive analysis of the cardiovascular impacts of MPs/NPs across species, highlighting significant implications for human health. By synthesizing findings from studies on aquatic and terrestrial organisms, including humans, this review offers insights into the ubiquity of MPs/NPs and their pathophysiological roles in cardiovascular systems. We demonstrated that exposure to MPs/NPs is linked to various cardiovascular ailments such as thrombogenesis, vascular damage, and cardiac impairments in model organisms, which likely extrapolate to humans. Our review critically evaluated methods for detecting MPs/NPs in biological tissues, assessing their toxicity, and understanding their behaviour within the vasculature. These findings emphasise the urgent need for targeted public health strategies and enhanced regulatory measures to mitigate the impacts of MP/NP pollution. Furthermore, the review underlined the necessity of advancing research methodologies to explore long-term effects and potential intergenerational consequences of MP/NP exposure. By mapping out the intricate links between environmental exposure and cardiovascular risks, our work served as a pivotal reference for future research and policymaking aimed at curbing the burgeoning threat of plastic pollution.

Primitive macrophages enable long-term vascularization of human heart-on-a-chip platforms.

The intricate anatomical structure and high cellular density of the myocardium complicate the bioengineering of perfusable vascular networks within cardiac tissues. In vivo neonatal studies highlight the key role of resident cardiac macrophages in post-injury regeneration and angiogenesis. Here, we integrate human pluripotent stem-cell-derived primitive yolk-sac-like macrophages within vascularized heart-on-chip platforms. Macrophage incorporation profoundly impacted the functionality and perfusability of microvascularized cardiac tissues up to 2 weeks of culture. Macrophages mitigated tissue cytotoxicity and the release of cell-free mitochondrial DNA (mtDNA), while upregulating the secretion of pro-angiogenic, matrix remodeling, and cardioprotective cytokines. Bulk RNA sequencing (RNA-seq) revealed an upregulation of cardiac maturation and angiogenesis genes. Further, single-nuclei RNA sequencing (snRNA-seq) and secretome data suggest that macrophages may prime stromal cells for vascular development by inducing insulin like growth factor binding protein 7 (IGFBP7) and hepatocyte growth factor (HGF) expression. Our results underscore the vital role of primitive macrophages in the long-term vascularization of cardiac tissues, offering insights for therapy and advancing heart-on-a-chip technologies.

Unsupervised Segmentation of 3D Microvascular Photoacoustic Images Using Deep Generative Learning.

Mesoscopic photoacoustic imaging (PAI) enables label-free visualization of vascular networks in tissues with high contrast and resolution. Segmenting these networks from 3D PAI data and interpreting their physiological and pathological significance is crucial yet challenging due to the time-consuming and error-prone nature of current methods. Deep learning offers a potential solution; however, supervised analysis frameworks typically require human-annotated ground-truth labels. To address this, an unsupervised image-to-image translation deep learning model is introduced, the Vessel Segmentation Generative Adversarial Network (VAN-GAN). VAN-GAN integrates synthetic blood vessel networks that closely resemble real-life anatomy into its training process and learns to replicate the underlying physics of the PAI system in order to learn how to segment vasculature from 3D photoacoustic images. Applied to a diverse range of in silico, in vitro, and in vivo data, including patient-derived breast cancer xenograft models and 3D clinical angiograms, VAN-GAN demonstrates its capability to facilitate accurate and unbiased segmentation of 3D vascular networks. By leveraging synthetic data, VAN-GAN reduces the reliance on manual labeling, thus lowering the barrier to entry for high-quality blood vessel segmentation (F1 score: VAN-GAN vs. U-Net = 0.84 vs. 0.87) and enhancing preclinical and clinical research into vascular structure and function.

Simultaneous sealing and bisection of porcine renal blood vessels, ex vivo, using a continuous-wave, infrared diode laser at 1470 nm.

Electrosurgical and ultrasonic devices are used in surgical procedures for hemostatic sealing and bisection of vascular tissues. Previous benchtop studies alternatively demonstrated successful infrared laser sealing and cutting of blood vessels, in a sequential, two-step approach. This study describes a smaller, laparoscopic device compatible design, and simultaneous approach to sealing and bisection of vessels, with potential optical feedback. A 1470-nm infrared diode laser sealed and bisected 40 porcine renal arteries, ex vivo. A reciprocating, side-firing, optical fiber, housed in a transparent square quartz optical chamber (2.7 × 2.7 × 25 mm outer dimensions), delivered laser energy over an 11 mm scan length, with a range of incident powers (41-59 W) and treatment times (5-21 s). Vessel diameters ranged from 2.5 to 4.8 mm. Vessel burst pressure measurements were performed on each cut end (n = 80) with success indicated by pressures exceeding 360 mmHg. All vessel ends were successfully sealed and bisected (80/80). The highest incident power, 59 W, yielded short treatment times of 5-6 s. Peak temperatures on the external chamber surface reached 103 oC. Time to cool down to body temperature measured 37 s. Infrared lasers simultaneously seal and bisect blood vessels, with treatment times comparable to, and temperatures and cooling times lower than reported for conventional devices. Future work will focus on integrating the fiber and chamber into a standard 5-mm-outer-diameter laparoscopic device. Customization of fiber scan length to match vessel size may also reduce laser energy deposition, enabling lower peak temperatures, treatment times, and cooling times.

An accurate unsupervised extraction of retinal vasculature using curvelet transform and classical morphological operators.

BACKGROUND: Many ophthalmic disorders such as diabetic retinopathy and hypertension can be early diagnosed by analyzing changes related to the vascular structure of the retina. Accuracy and efficiency of the segmentation of retinal blood vessels are important parameters that can help the ophthalmologist to better characterize the targeted anomalies. METHOD: In this work, we propose a new method for accurate unsupervised automatic segmentation of retinal blood vessels based on a simple and adequate combination of classical filters. Initially, contrast of vessels in retinal image is significantly improved by adding the Curvelet Transform to commonly used Contrast-Limited Adaptive Histogram Equalization technique. Afterwards, a morphological operator using Top Hat is applied to highlight vascular network. Then, a global threshold-based Otsu technique using minimum of intra-class variance is applied for vessel detection. Finally, a cleanup operation based on Match Filter and First Derivative Order Gaussian with fixed parameters is used to remove unwanted or isolated segments. We test the proposed method on images from two publicly available STARE and DRIVE databases. RESULTS: We achieve in terms of sensitivity, specificity and accuracy the respective average performances of 0.7407, 0.9878 and 0.9667 on the DRIVE database, then 0.7028, 0.9755 and 0.9507 on the STARE database. CONCLUSIONS: Compared to some recent similar work, the obtained results are quite promising and can thus contribute to the optimization of automatic tools to aid in the diagnosis of eye disorders.

Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer's disease.

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n = 6 Alzheimer's disease (AD), and n = 6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases. Tau-positive vessels are enriched for tau at levels higher than the surrounding tissue and appear to affect arterioles across cortical layers (I-V). Further, vessels isolated from these AD tissues were enriched for N-terminal tau and tau phosphorylated at T181 and T217. Importantly, tau-positive vessels are associated with local areas of increased tau neurofibrillary tangles. This suggests that accumulation of tau around blood vessels may reflect a local clearance failure. In sum, these data indicate that tau, like amyloid beta, accumulates along blood vessels and may exert a significant influence on vasculature in the setting of AD.

Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer's disease.

White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's disease. Despite their frequent appearance and their association with cognitive decline, the molecular factors contributing to WMHs remain unclear. In this study, we investigated the transcriptomic profiles of two commonly affected brain regions with coincident AD pathology-frontal subcortical white matter (frontal-WM) and occipital subcortical white matter (occipital-WM)-and compared with age-matched healthy controls. Through RNA-sequencing in frontal- and occipital-WM bulk tissues, we identified an upregulation of genes associated with brain vasculature function in AD white matter. To further elucidate vasculature-specific transcriptomic features, we performed RNA-seq analysis on blood vessels isolated from these white matter regions, which revealed an upregulation of genes related to protein folding pathways. Finally, comparing gene expression profiles between AD individuals with high- versus low-WMH burden showed an increased expression of pathways associated with immune function. Taken together, our study characterizes the diverse molecular profiles of white matter changes in AD compared to normal aging and provides new mechanistic insights processes underlying AD-related WMHs.

Report of intraosseous intravascular papillary endothelial hyperplasia associated with an odontogenic cyst in the maxilla and literature review.

Intravascular papillary endothelial hyperplasia (IPEH) represents an uncommon reactive endothelial hyperplastic proliferation. A 46-year-old man experienced increased volume in the right maxilla, elevation of the nasal ala, and swelling of the hard palate with a reddish hue for 3 months. Computed tomography revealed an expansive hypodense region and cortical bone destruction associated with an impacted supernumerary tooth and an endodontically treated tooth. Under the differential diagnoses of a radicular cyst, dentigerous cyst, and ameloblastoma, an exploratory aspiration and incisional biopsy were performed. This revealed the formation of blood vessels of various diameters lined by endothelium, forming intravascular papillae positive for CD-34. The definitive diagnosis was IPEH, and the patient was treated by embolization and surgery. Histological analysis confirmed the presence of IPEH associated with an odontogenic cyst. After 12 months of follow-up, no recurrence was observed. Also, we reviewed case reports of IPEH affecting the maxilla and mandible. Fourteen intraosseous cases were reported in the maxilla and mandible, with a preference for males and affecting a wide age range. Complete surgical excision was the treatment of choice, and recurrences were not reported. The pathogenesis of IPEH is controversial and may originate from trauma or inflammatory processes. To the best of our knowledge, this is the first report of an association of IPEH with an odontogenic cyst. The importance of IPEH in the differential diagnosis of intraosseous lesions in the jaws is emphasized, and preoperative semiotic maneuvers are needed to prevent surgical complications.

Dental Pulp Vascular Response to Early Stages of Caries.

OBJECTIVES: During caries progression, dental pulp is increasingly pathologically affected. Since the accurate assessment of pulp is of vital importance in clinical decision-making, this study aimed to evaluate pulpal condition in the early stages of caries via laser Doppler (LD) flowmetry and histologic analysis and determine their agreement. METHODS: Fourteen patients with severe dental crowding were included. Prior to extractions and orthodontic treatment, dental pulp condition of 52 premolars was evaluated via LD flowmetry. Teeth were assessed for the presence of caries and lesions were graded according to the International Caries Detection and Assessment System (ICDAS). After extractions, teeth were split and histologically stained for endothelial cells with anti-von Willebrand factor and Movat pentachrome for collagen. Volume densities of vessels (Vvasc) and collagen were calculated. RESULTS: There was a significant negative correlation between LD flow and Vvasc of the dental pulp with ICDAS grade. Pulpal LD flow and Vvasc in teeth with the initial lesion were increased, decreasing with progressing stages of caries. A significant positive correlation between the the pulpal LD flow and Vvasc, and a negative correlation of LD flow with collagen fibre density were noted. CONCLUSIONS: Caries affects the physiology of the dental pulp, initially with increasing vascularity, and decreasing vascularity at later stges of caries progression. Collagen contents increase with grades of ICDAS. LD flow shows good agreement with the histologic constitution of the dental pulp. Use of clinical measurements of pulpal LD flow could provide a good noninvasive indication of pulpal vascular state and its health.

Retinal Blood Vessel Formation in the Macula Following Intravitreal Ranibizumab Injection for Aggressive Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Recently, anti-vascular endothelial growth factor (VEGF) drugs have been widely used for ROP to inhibit abnormal retinal angiogenesis. However, there is a concern that such drugs potentially also affect normal retinal vascular development. We report a case of blood vessel growth across the macula after anti-VEGF treatment for zone I aggressive ROP. A 25-week-old female infant was administered 0.2 mg of ranibizumab for bilateral aggressive ROP in both eyes at 33 weeks of postmenstrual age. Under normal development, retinal blood vessels do not grow into the center of the future macular region. After five weeks, however, a horizontal blood vessel sprouted from the optic disc and extended across the macula in the right eye. The blood vessel ran straight to the vascular-avascular juncture by 41 weeks of postmenstrual age during the follow-up period. While the focus has been on arresting retinal vascular development through VEGF inhibition, anti-VEGF treatment may induce vascular abnormalities in patients with severe ROP. Infants with retinal vascular abnormalities should be carefully monitored for their visual prognosis.

Anatomy of blood microcirculation in the pig epicardial ganglionated nerve plexus.

Embolization of coronary arteries and their terminal arterioles causes ischemia of all tissues distributed within a cardiac wall including the intrinsic cardiac ganglionated nerve plexus (ICGP). The disturbed blood supply to the ICGP causes chronic sympathetic activation with succeeding atrial and ventricular arrhythmias. This study analyses the anatomy of microcirculation of epicardial nerves and ganglia using the hearts of 11 domestic pigs. Our findings demonstrate that thicker epicardial nerves are normally supplied with blood via 12 epineural arterioles penetrating the endoneurium regularly along a nerve, and forming an endoneurial capillary network, which drains the blood into the myocardial blood flow. The mean diameter of intraneural capillaries was 7.2 ± 0.2 µm, while the diameters of arterioles were 25.8 ± 0.7 µm and involved 45 endothelial cells accompanied by circular smooth muscle cells. Usually, two or three arterioles with a mean diameter of 28.9 ± 1.7 µm supplied blood to any epicardial ganglion, in which arterioles proceeded into a network of capillaries with a mean diameter of 6.9 ± 0.3 µm. Both the epicardial nerves and the ganglia distributed near the porta venarum of the heart had tiny arterioles that anastomosed blood vessels from the right and the left coronary arteries. The density of blood vessels in the epicardial nerves was significantly lesser compared with the ganglia. Our electron microscopic observations provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation. STRUCTURED ABSTRACT: This study details the anatomy of microcirculation of epicardial nerves and ganglia, from which intracardiac nerves and bundles of nerve fibers extend into all layers of the atrial and ventricular walls in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our findings provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation.

Breathing new life into tissue engineering: exploring cutting-edge vascularization strategies for skin substitutes.

Tissue-engineered skin substitutes (TESS) emerged as a new therapeutic option to improve skin transplantation. However, establishing an adequate and rapid vascularization in TESS is a critical factor for their clinical application and successful engraftment in patients. Therefore, several methods have been applied to improve the vascularization of skin substitutes including (i) modifying the structural and physicochemical properties of dermal scaffolds; (ii) activating biological scaffolds with growth factor-releasing systems or gene vectors; and (iii) developing prevascularized skin substitutes by loading scaffolds with capillary-forming cells. This review provides a detailed overview of the most recent and important developments in the vascularization strategies for skin substitutes. On the one hand, we present cell-based approaches using stem cells, microvascular fragments, adipose tissue derived stromal vascular fraction, endothelial cells derived from blood and skin as well as other pro-angiogenic stimulation methods. On the other hand, we discuss how distinct 3D bioprinting techniques and microfluidics, miRNA manipulation, cell sheet engineering and photosynthetic scaffolds like GelMA, can enhance skin vascularization for clinical applications. Finally, we summarize and discuss the challenges and prospects of the currently available vascularization techniques that may serve as a steppingstone to a mainstream application of skin tissue engineering.

Cancer metastasis through the lymphatic versus blood vessels.

Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.

Endothelial Cell Dysfunction: Onset, Progression, and Consequences.

Endothelial cell dysfunction is a complex process involving various causes, early and late events, and subsequent consequences. This review provides an overview of each aspect and outlines therapeutic interventions targeting these stages. Causes of endothelial dysfunction encompass a spectrum of risk factors including hypertension, diabetes, smoking, obesity, inflammation, oxidative stress, and genetic predispositions. Early events such as endothelial activation, inflammatory response, and dysregulated vasomotor tone precede late events like oxidative stress, endothelial apoptosis, and microvascular rarefaction. The consequences include endothelial remodelling, neovascularization, organ dysfunction, and clinical manifestations, highlighting the diverse impacts across multiple systems. While depicted linearly, the progression of endothelial dysfunction is dynamic, influenced by various factors such as the underlying cause and affected vascular bed. Understanding these dynamics is crucial for tailoring therapeutic interventions, ranging from lifestyle modifications to targeted therapies, to address the underlying causes and effects effectively. Here we provide comprehensive understanding of endothelial cell dysfunction that is essential for developing strategies to mitigate the impact of this dysregulation on health and cardiovascular diseases progression.

The impact of temperature on vascular function in connection with vascular laser treatment.

Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment.

Comparison of the effects of platelet-rich plasma and platelet-rich fibrin on the healing process of a rat's mucosal wound.

Due to the problems associated with the use of PRP, a platelet concentrates without coagulation factors, called platelet-rich fibrin (PRF), has been developed that, in addition to tissue regeneration and wound healing, contains more white blood cells (WBCs), which are important in the wound healing process. In this study, the effect of these two platelet-rich plasmas on the thickness of the epithelium, the number of blood vessels and fibroblasts, and wound area were measured in two groups of PRP and PRF and at different periods. We divided the rats into three groups: the control group, the group receiving PRP, and the group receiving PRF. The results showed a significant difference in the number of fibroblasts, wound area, thickness of epithelium, and number of vessels in all three groups. Based on the results, the use of PRP and PRF in wounds can accelerate the formation of epithelium, create better and more blood vessels, create a platform for the migration and formation of fibroblast cells, and facilitate faster wound closure. Also, comparing PRP and PRF, it can be concluded that, finally, PRF acts better than PRP in epithelialization.

Modeling and experimental study of the intervention forces between the guidewire and blood vessels.

A profound investigation of the interaction mechanics between blood vessels and guidewires is necessary to achieve safe intervention. An interactive force model between guidewires and blood vessels is established based on cardiovascular fluid dynamics theory and contact mechanics, considering two intervention phases (straight intervention and contact intervention at a corner named "J-vessel"). The contributing factors of the force model, including intervention conditions, guidewire characteristics, and intravascular environment, are analyzed. A series of experiments were performed to validate the availability of the interactive force model and explore the effects of influential factors on intervention force. The intervention force data were collected using a 2-DOF mechanical testing system instrumented with a force sensor. The guidewire diameter and material were found to significantly impact the intervention force. Additionally, the intervention force was influenced by factors such as blood viscosity, blood vessel wall thickness, blood flow velocity, as well as the interventional velocity and interventional mode. The experiment of the intervention in a coronary artery physical vascular model confirms the practicality validation of the predicted force model and can provide an optimized interventional strategy for vascular interventional surgery. The enhanced intervention strategy has resulted in a considerable reduction of approximately 21.97 % in the force exerted on blood vessels, effectively minimizing the potential for complications associated with the interventional surgery.

Exploring vasculogenesis in the normal human kidney and clear cell renal cell carcinoma: insights from development to tumor progression and biomarkers for therapy response.

Vasculogenesis, which refers to the development of blood vessels from precursor cells, is a process that occurs predominantly during early embryonic life. It plays a crucial role in the establishment of the primitive vascular network. Vasculogenesis diminishes throughout the fetal vascular remodeling process, giving way to angiogenesis, which becomes the predominant mechanism after birth. At first, the development of the kidney's blood vessels depends on vasculogenesis, and then both vasculogenesis and angiogenesis happen simultaneously. Both processes are necessary for the normal development of the renal vasculature. Although the kidneys are highly vascularized, our understanding of normal kidney vasculogenesis is still incomplete. This lack of knowledge may explain the limited data available on the role of vasculogenesis in the progression and spread of renal cancers. In other types of cancer, researchers have well documented the phenomenon of tumor vasculogenesis. However, there is currently limited and fragmented information about the occurrence of clear-cell renal cell carcinomas (cc-RCC). In this article, we provide a comprehensive review of the current understanding of normal kidney vasculogenesis and vasculogenic pathways in clear cell renal cell carcinoma (cc-RCC). We specifically focus on cellular precursors, growth factors, and the influence of the normal and tumor environments on these processes. It will carefully look at how tumor vasculogenesis might affect the growth and metastasis of clear cell renal cell carcinoma (cc-RCC), as well as how it might affect the effectiveness of drugs and the development of therapy resistance.