Influencing factors of poor response to anti-vascular endothelial growth factor drug therapy for wet age-related macular degeneration and therapeutic strategy of targeting pericytes / 国际眼科杂志(Guoji Yanke Zazhi)

With the increasing aging population, the incidence of wet age-related macular degeneration(wARMD)is gradually rising. The formation of neovascularization leads to recurrent hemorrhage in the macular region, which is one of the main causes of blindness in the elderly. Currently, the primary clinical treatment for wARMD is intravitreal injection of anti-vascular endothelial growth factor(VEGF)drugs. However, there are still some patients who have poor or no response to anti-VEGF drugs, resulting in suboptimal or ineffective clinical outcomes. Analyzing the specific influencing factors will be beneficial in guiding clinical decision-making. This article reviews the impact of factors such as advanced age, treatment duration, number of injections, characteristics of neovascular lesions, macular structure, intraocular cytokine levels, and genetics on the response to anti-VEGF therapy. In addition, recent studies have found that pericytes, as cellular components of microvascular walls, can influence the sensitivity to anti-VEGF therapy. This review summarizes the current research on the mechanisms of pericytes in poor or non-response to anti-VEGF therapy and discusses targeted strategies focusing on pericytes.

Vasa Vasorum in Saphenous Vein for CABG: A Review of Morphological Characteristics

ABSTRACT This short article discusses selected scanning electron microscope and transmission electron microscope features of vasa vasorum including pericytes and basement membrane of the human saphenous vein (SV) harvested with either conventional (CON) or no-touch (NT) technique for coronary artery bypass grafting. Scanning electron microscope data shows the general damage to vasa vasorum of CON-SV, while the transmission electron microscope data presents ultrastructural features of the vasa in more detail. Hence there are some features suggesting pericyte involvement in the contraction of vasa blood vessels, particularly in CON-SV. Other features associated with the vasa vasorum of both CON-SV and NT-SV preparations include thickened and/or multiplied layers of the basement membrane. In some cases, multiple layers of basement membrane embrace both pericyte and vasa microvessel making an impression of a "unit" made by basement membrane-pericyte-endothelium/microvessel. It can be speculated that this structural arrangement has an effect on the contractile and/or relaxing properties of the vessels involved. Endothelial colocalization of immunoreactive inducible nitric oxide synthase and endothelin-1 can be observed (with laser confocal microscope) in some of the vasa microvessels. It can be speculated that this phenomenon, particularly of the expression of inducible nitric oxide synthase, might be related to structurally changed vasa vessels, e.g., with expanded basement membrane. Fine physiological relationships between vasa vasorum endothelium, basement membrane, pericyte, and perivascular nerves have yet to be uncovered in the detail needed for better understanding of the cells'specific effects in SV preparations for coronary artery bypass grafting.

Research progress on the role of pericytes in neovascular eye diseases / 国际眼科杂志(Guoji Yanke Zazhi)

@#Neovascular eye disease, which is characterized by pathological neovascular formation, is a major disease threatening visual health. In recent years, neovascular eye disease has become a serious public health problem and attracted widespread attention, with the incidence increasing year by year. Pathological neovascularization is formed under the mutual inclusion and interaction of a variety of cellular components and pathological factors. It is often difficult to achieve ideal therapeutic effect if we intervene only one of the factors. Therefore, it is in an urgent need to conduct a more in-depth study in the pathological process of neovascularization and explore new factors that regulate neovascularization in order to find more effective treatments of neovascular eye diseases. In recent years, pericyte has been proved to play important roles in the occurrence and development of various neovascular eye diseases and interventions for pericytes will affect the pathological process of these diseases. This article will review the specific roles of pericytes in some common neovascular eye diseases and the factors regulating pericytes in these diseases, which would provide new ideas in the treatment of neovascular eye diseases.

COVID-19: a closer look at the pathology in two autopsied cases. Is the pericyte at the center of the pathological process in COVID-19?

We performed autopsies on two cases of COVID-19. The microcirculations of all organs were the site of the pathological findings. Thrombotic microangiopathy was found in the brain and also the kidneys. Vasculitis was also a feature of the autopsy findings, together with portal triaditis of the liver. The major pathological findings in both cases were fibrin deposits. Within the lung, the fibrin deposits were observed in the alveolar microcirculation in sub-endothelial locations of capillaries, arterioles, post capillary venules, and the adventitia of larger vessels. These fibrin deposits in the lungs occurred at the sites where pericytes are located in these vessels. The pericyte with its high concentration of ACE-2 receptors and its procoagulant state may represent one of the primary sites of action of SARS-CoV-2. A review of pericytes in health and disease is undertaken. COVID-19 is a disease of the microcirculation.

Investigação de pericitos e fotobiomodulação no reparo tecidual em modelo murino diabético / Investigation of pericytes under effect of photobiomodulation in tissue repair in a diabetic murine mice

Em indivíduos com diabetes mellitus (DM) o reparo tecidual cutâneo atrasado representa um desafio para o sistema de saúde. Evidências recentes mostram o potencial da fotobiomodulação (PBM, do inglês, photobiomodulation) em induzir a diferenciação de células-tronco em múltiplos tecidos. Os pericitos são células-tronco perivasculares com ampla plasticidade, podendo ser considerados alvos potenciais para a PBM durante o reparo tecidual. Assim, o objetivo deste estudo foi investigar o efeito da PBM na modulação de células indiferenciadas em feridas de camundongos em condição sistêmica análoga ao DM tipo-II. Trata-se de um estudo in vivo (CEUA#62/2019) utilizando camundongos transgênicos diabéticos induzidos artificialmente e com marcação endógena para pericitos (NG2+/DsRed+; Nestina+/GFP+ & NG2+/DsRed+) e células mesenquimais indiferenciadas (Nestina+/GFP+). Foram realizadas bilateralmente feridas no dorso dos camundongos, e as mesmas foram submetidas ou não a PBM e avaliadas nos tempos experimentais 1, 3 e 7 dias. O reparo tecidual foi acompanhado por morfometria, avaliação de fluxo sanguíneo, análises histológicas nos tempos 1, 3 e 7 dias, além de identificação dos pericitos por microscopia confocal ao final de 3 e 7 dias. Os dados obtidos foram submetidos à análise estatística. As análises morfométricas e histológicas mostraram maior efeito de reparo nas feridas submetidas a PBM, onde a média de área remanescente após 1 de PBM foi 73% da medida de área total inicial no grupo PBM e 86,21% no controle (p=0,0257); aos 3 dias, foram 66,98% e 87,49% respectivamente (p=0,026) e aos 7 dias, 25,54% no grupo PBM e 39,43% no controle (p<0,05). A perfusão sanguínea foi maior nas áreas das feridas quando comparadas a pele íntegra, no entanto, não foram observadas diferenças entre as feridas submetidas ou não a PBM. Por outro lado, foram observadas nestas (PBM), maiores quantidades de células mesenquimais indiferenciadas (Nestina+/GFP+) e de pericitos tipo-I (NG2+/DsRed+) após 7 dias. A utilização de PBM em processos de reparo tecidual em modelo diabético de feridas demostraram resultados significativos tanto clínicos com a nível celular, envolvendo em grande parte as células mesenquimais (nestina+/GFP+) e pericitos (NG2+/DsRed+). Conhecer os mecanismos celulares de ação da PBM em feridas de modelo diabético permite controlar esse processo, além de explorar essa técnica e abrir caminhos para investigação de outras ferramentas e protocolos úteis para o tratamento de feridas nestes indivíduos afetados.

In individuals with diabetes mellitus (DM) delayed cutaneous tissue repair represents a challenge for the health system. Recent evidence shows the potential of photobiomodulation (PBM) to induce stem cell differentiation in multiple tissues. Pericytes, in turn, are perivascular stem cells with wide plasticity and can be considered potential targets for PBM during tissue repair. The objective of this study was to investigate the role of PBM in stem cell modulation in wounds of mice under systemic condition analogous to type-II DM. This is an in vivo study (Ethical protocol: CEUA#62/2019) using artificially induced transgenic diabetic mice with endogenous labeling for pericytes (NG2+/DsRed+; Nestin+/GFP+ & NG2+/DsRed+) and undifferentiated mesenchymal cells (Nestin+/GFP+). Wounds on the mice's back were bilaterally performed, and then submitted or not to laser therapy and evaluated at experimental times 1, 3 and 7 days. Tissue repair was followed by periodic measurements of wound diameter, blood flow assessment, histological analysis and screening of pericytes by confocal microscopy at the end of each experimental time. The data obtained were submitted to statistical analysis. The histologic and morphometric analysis showed a greater repair effect in wounds submitted to PBM, where the average area remaining after 1 day of laser application was 73% of the initial total area measurement in the PBM group, and 86.21% in the control (p= 0.0257); at 3 days, they were 66.98% and 87.49% respectively (p= 0. 026), and at 7 days, 25.54% in the PBM group and 39.43% in the control (p<0.05). Blood perfusion was greater in wound areas when compared to intact skin, however, no statistical differences were observed between wounds submitted or not to PBM. On the other hand, larger amounts of undifferentiated mesenchymal cells (Nestin+/GFP+) and type-I pericytes (NG2+/DsRed+) were observed in these wounds after 7 days. The use of PBM in tissue repair processes in a diabetic wound healing model showed significant clinical and cellular results, involving mostly mesenchymal cells (nestin+/GFP+) and pericytes (NG2+/DsRed+). Knowing the cellular mechanisms of action of PBM in wounds of diabetic, allows better management of the therapy, also it opens paths for the investigation of other tools and protocols useful for the treatment of wounds in DM individuals.

Role of pericytes in the pathogenesis of cerebral small vessel disease / 国际脑血管病杂志

Pericytes are located between capillary endothelial cells, astrocytes and neurons. They have many functions such as maintaining the integrity of blood-brain barrier and regulating cerebral blood flow. Loss of pericytes can lead to pathological processes such as brain microcirculation dysfunction and blood-brain barrier destruction, and is associated with a variety of diseases, but there are few studies on the correlation between them and cerebral small vessel disease. This article mainly reviews the role of pericytes in the pathogenesis of cerebral small vessel disease.

Establishment of three-dimensional model of rat retinal angiogenesis <i>in</i> <i>vitro</i> based on endothelial cells and pericytes / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To establish three-dimensional(3D)model of rat retinal angiogenesis <i>in</i> <i>vitro</i> based on retinal microvascular endothelial cells(ECs)and retinal microvascular pericytes(RMPs). <p>METHODS: The identified ECs and RMPs of third generation to seventh generation were used for research after isolated, purified and cultured. The cells were stained with cell tracer. Then, it were mixed and inoculated on Matrigel by the surface culture method for dynamic observation. The expression of VEGF-A was assessed during angiogenesis. <p>RESULTS: At 12h of co-culture, RMPs were recruited by ECs and gathered into cell masses with different sizes. At 24h, ECs/RMPs formed a complex 3D vascular spline network. At 48h, the reticular structure disintegrated obviously, and only a small amount of incomplete and simple reticular structure remained. At 72h, the vascular spline cable network disintegrated completely. In the development of 3D model, the expression of VEGF-A increased, but decreased when it degenerated. <p>CONCLUSION: This study successfully established a 3D model of rat retinal angiogenesis <i>in</i> <i>vitro</i> based on ECs and RMPs.

Malignant glomus tumor of the index finger

Glomus tumor (GT) is a benign mesenchymal tumor with an estimated incidence of 1.5 to 2% of soft tissue tumors. The majority of glomus tumors are benign and are mostly seen in the superficial skin & soft tissue of upper and lower distal extremity. The malignant variant of the glomus tumor is scarce. We report a case of a recurrent glomus tumor diagnosed in a 28-year-old male patient, who complained of painful swelling in the proximal phalanx of the right index finger. The magnetic resonance imaging of the hand revealed a well-defined multilobulated soft tissue mass at the palmar aspect of the 2nd digit along the shaft of the proximal phalanx. Histopathology revealed a well-circumscribed tumor arranged in solid sheets, nests and cords interconnect by vessels of varying size. The tumor cells were round to oval, showed moderate nuclear pleomorphism, eosinophilic cytoplasm, atypical mitoses (>5/10HPF), and necrosis. Immunohistochemically tumor cells reveal diffuse and strong cytoplasmic positivity with smooth muscle actin (SMA). Based on histomorphology and immunohistochemistry, a final diagnosis of malignant glomus tumor was made. We report this case due to its rarity, and it to be included among the differential if the lesion is painful and recurrent.

In vitro hematopoietic support of human umbilical cord blood cd34+ cells by human skeletal muscle-derived pericytes/perivascular cells / 中国组织工程研究

BACKGROUND: Perivascular cells have been shown to be the precursor cells of mesenchymal stem cells, which regulate the behavior of hematopoietic stem cells and support hematopoiesis through cell-to-cell contact or paracrine effects. Hematopoietic support of human skeletal muscle-derived pericytes/perivascular cells (hMD-PCs) remains to be studied. OBJECTIVE: To identify the biological characteristics of hMD-PCs isolated from human skeletal muscle and to study their supporting effect on umbilical cord blood CD34+ cells in vitro. METHODS: (1) hMD-PCs with phenotype CD146+ CD56-CD34-CD144-CD45- were sorted from human skeletal muscle by enzymatic digestion and multiparameter fluorescence-activated cell sorting, and their biological characteristics were identified. (2) The in vitro culture system of umbilical cord blood CD34+ cells co-cultured with human CD146+ hMD-PCs (experimental group) or with human bone marrow mesenchymal stem cells (positive control group) was established. After 1, 2 and 4 weeks of co-culture, the number of cells, the colony formation ability and immunophenotype were measured and statistically analyzed. RESULTS AND CONCLUSION: (1) CD146+ hMD-PCs were sorted by multiparameter fluorescence-activated cell sorting and the purity was (91.5±1.85)% (n=5). CD146+ hMD-PCs expressed mesenchymal surface markers CD73, CD90, CD105, CD44, and did not express hematopoietic cell and endothelial cell markers CD45, CD34, and CD31. After induced culture, CD146+ hMD-PCs could differentiate into osteoblasts, chondrogenesis, adipocytes and myoblasts. (2) There were no significant differences in the cell number, colony f ormation ability or immunophenotype (CD45+, CD34+ CD33-, CD14+, CD10+/CD19+) between experimental and positive control groups (P > 0.05, n=6). The number of cells in the blank control group without feeder was significantly decreased at 1 week of culture, and there was almost no cell survival at 2 weeks of culture. (3) In summary, CD146+ hMD-PCs, like human bone marrow mesenchymal stem cells, have hematopoietic support capacity in vitro.

Potentials of pericytes in orthopedics / 中国组织工程研究

BACKGROUND: Pericytes and other perivascular stem cells are gaining increasing attention in bone tissue engineering. Pericytes have been long thought to regulate blood pressure and promote angiogenesis. However, it is now considered to have the characteristics of mesenchymal stem cells, including pluripotency, self-renewal, immune regulation, and tissue repair, showing strong regenerative potential in common orthopedic diseases such as fractures, nonunion, vertebral fusion, ligament rupture, and cartilage injury. OBJECTIVE: To summarize the related applications of pericytes in orthopedics, and to explore mechanisms, strengths and limitations.METHODS: With “pericytes, perivascular stem cells, repair, therapy, orthopedics” as Chinese and English retrieval terms, we systematically searched databases including PubMed, Web of Science, CNKI and WanFang, from inception to August 2019 for the articles concerning the treatment of orthopedic diseases with pericytes. A total of 112 related documents were retrieved. After reading the full text, 55 eligible documents were selected. RESULTS AND CONCLUSION: Pericytes are a kind of emerging stem cells that have been reported in many studies regarding the treatment of orthopedic diseases, and have a greatly therapeutic prospect. There are abundant pericytes in the body with no need for in vitro culture. The repair mechanism of pericytes is mainly related to paracrine mediation, with self-differentiation as a secondary mechanism. However, its specific mechanism remains unclear, which needs further investigations.

THE EFFECT OF LOW INTENSITY ELECTROMAGNETIC FIELD (EMF) EXPOSURE ON PERICYTES IN BRAIN TISSUES AND BLOOD OXIDATIVE STRESS LEVEL IN RATS (Kesan Pendedahan Medan Elektromagnetik Intensiti Rendah (Emf) Terhadap Perisit Tisu Otak Dan Aras Stres Oksidatif Darah Tikus) / Jurnal Sains Kesihatan Malaysia

@#Studies on the potential effect of EMF exposure on permeability of the blood-brain barrier (BBB) in humans are virtually absent. This study was conducted to study the effect of EMF exposure on pericytes in brain tissues and its effect on oxidative stress level in the blood through total protein and malondialdehyde (MDA). About 16 male rats (Wistar) were used and divided into two groups which were negative control and treatment group. In negative control group, the animals were placed in a solenoid without any EMF exposure for 3 hours daily for 5 days. In the treatment group, the animals were placed in a solenoid with 0.3 mT EMF exposure for the same time duration. On day 3 and day 5, animals were sacrificed and the brain was removed for histological examination while on day 1, day 3 and day 5, the blood was collected for biochemistry analysis. Histological observation showed the presence of morphological changes in the brain tissues of rats that exposed to EMF. Statistical analysis showed that there is no significant decrease in total protein (p>0.05) between negative control group and treatment group. Meanwhile, MDA level in blood showed a significant increase in treatment group (p<0.05) as compared to the negative control group. The result obtained in this study, suggest that the exposure to EMF can cause changes to the morphology of pericytes in brain tissues, and can increase the MDA level in blood of rats.

A Simple and Nonenzymatic Method to Isolate Human Corpus Cavernosum Endothelial Cells and Pericytes for the Study of Erectile Dysfunction

Pericyte Plasticity in the Brain / 神经科学通报·英文版

Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.

Advance in Pericytes and Related Angiogenic Signaling Pathways after Cerebral Ischemia (review) / 中国康复理论与实践

Pericytes, endothelial cells (EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units (NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes. This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.

Advance in Pericytes and Related Angiogenic Signaling Pathways after Cerebral Ischemia (review) / 中国康复理论与实践

Pericytes, endothelial cells (EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units (NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes. This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.

Changes of BKCa on vascular striaepericytes of D-galactose-induced aging model in guinea pigs / 中华耳鼻咽喉头颈外科杂志

Objective@#The aging model of guinea pigs induced by D-galactose was set up to investigate the changes of BKCa expression and function on cochlear pericytes and their relationship with age-related hearing loss.@*Methods@#Thirty healthy 8-week-old guinea pigs were randomly divided into three groups, with 10 in each group: D-galactose aging model group, subcutaneous injection of D-galactose (500 mg/kg) daily for 6 weeks; saline control group, the same amount of saline was injected into the neck of the aging model group for 6 weeks; the blank control group, no treatment was performed. The threshold of auditory brainstem response (ABR) was detected. The content of BKCa in the perivascular cells of the guinea pig cochlear cells was detected by immunofluorescence technique. The changes of peripheral current density and BKCa current were detected by patch clamp technique. The data were analyzed by GraphPad Prism software.@*Results@#Compared with the saline group and the control group, the ABR threshold and the amplitude of the wave I were significantly decreased in the aging model group, and the difference was statistically significant (P<0.01). Compared with the control group, the expression of BKCa in the vascular pericytes of guinea pigs in the aging model group was significantly reduced (1.00±0.08 vs 0.27±0.03,the difference was statistically significant P<0.01), and the cell current density and BKCa net current value were also significantly reduced with statistically significant (P<0.01).@*Conclusions@#D-galactose can successfully induce guinea pig aging model, in which BKCa expression decreases and net current value decreases in pericytes of cochlear striavascularis, and changes in BKCa expression and function may be related to age-related hearing loss.

Progress in research on pericytes of microvessels in related diseases / 医学研究生学报

Pericytes are a type of cell similar to vascular smooth muscle cells, named after the localization of capillaries and microvascular basement membranes. Pericytes were originally shown to be involved in vasoconstriction, regulating blood flow to local microvasculature. In recent years, its functions of regulating angiogenesis and promoting vascular maturation have been successively recognized. Many microvascular lesions are accompanied by pericyte cell structural and functional abnormality. Therefore, the regulation of pericytes has received extensive attention, but many mechanisms have not yet been elucidated. The review summarizes the role of pericytes in microvascular diseases such as cranial neuropathy, cardiovascular disease, diabetic vascular changes and tumors.

Relationship between Changes of Pericyte Number and Wound Age during Repair of Skeletal Muscle Contusion in Mice / 法医学杂志

Objective To observe the change pattern of pericyte number at different time periods after mice skeletal muscle contusion and discuss its role in wound age estimation. Methods A mice gastrocnemius muscle contusion model was established. The form and number changes of pericytes at 1, 3, 5, 7, 9, 14, and 28 d post-injury were detected by multiple immunofluorescence staining. Results Compared with the slender shape of pericytes in normal skeletal muscles, pericytes in the contusion area had increased volume, rounder form and a round nuclei. Part of pericytes were found to express satellite cell markers paired-box transcription factor （Pax7） or myoblast determination 1 （MyoD1）. The changes of pericyte number in skeletal muscles after contusion were time-dependant, and showed unimodal distribution with the extension of wound age. In the central contusion area, the number of pericytes peaked at 5 d post-injury while in the peripheral contusion area, the number of pericytes peaked at 5 d and 7 d post-injury. Conclusion The number of pericytes in contusion area varies time-dependently after skeletal muscle contusion in mice and might be a reference index for muscle wound age estimation, and is involved in the repair and regeneration of skeletal muscle injury.

Pathophysiology of Diabetic Retinopathy: The Old and the New

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.