《血管生成》是一本国际同行评审期刊，致力于发表高质量的原创文章和评论，了解在生理和病理条件下调节血管生成的细胞和分子机制。作为代表全方位血管生成研究的快速交流的中心来源，这本多学科期刊发表使用分子、体外、动物模型系统和血管生成疾病临床研究的创新实验研究。血管生成还报道了促进或抑制血管生成的新治疗方法以及疾病诊断和预后的新标志物和技术。

Angiogenesis is an international peer-reviewed journal dedicated to publishing high-quality original research and reviews that explore the cellular and molecular mechanisms regulating angiogenesis under physiological and pathological conditions. As a central source for rapid communication in the field of angiogenesis research, this multidisciplinary journal publishes innovative experimental studies utilizing molecular, in vitro, animal model systems, and clinical research on angiogenesis-related diseases. Angiogenesis also reports on new therapeutic approaches that promote or inhibit angiogenesis, as well as novel biomarkers and techniques for disease diagnosis and prognosis.

《Angiogenesis》是一本国际同行评审期刊，专注于发表高质量的原创研究和评论，探讨在生理和病理条件下调节血管生成的细胞和分子机制。作为血管生成研究的快速交流中心，这本多学科期刊发表基于分子、体外实验、动物模型和临床研究的创新实验成果。《Angiogenesis》还报道了促进或抑制血管生成的新治疗方法，以及疾病诊断和预后的新标志物和技术。

Angiogenesis

In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

Andrew C. Dudley

Arjan W. Griffioen

Pathological angiogenesis: mechanisms and therapeutic strategies

病理性血管生成：机制与治疗策略

Loss of visual acuity in neovascular age-related macular degeneration (nAMD) occurs when factors activate choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelium into the sensory retina and develop into choroidal neovascularization (CNV). Active Rac1 (Rac1GTP) is required for CEC migration and is induced by different AMD-related stresses, including vascular endothelial growth factor (VEGF). Besides its role in pathologic events, Rac1 also plays a role in physiologic functions. Therefore, we were interested in a method to inhibit pathologic activation of Rac1. We addressed the hypothesis that IQGAP1, a scaffold protein with a Rac1 binding domain, regulates pathologic Rac1GTP in CEC migration and CNV. Compared to littermate Iqgap1+/+, Iqgap1-/- mice had reduced volumes of laser-induced CNV and decreased Rac1GTP and phosphorylated VEGFR2 (p-VEGFR2) within lectin-stained CNV. Knockdown of IQGAP1 in CECs significantly reduced VEGF-induced Rac1GTP, mediated through p-VEGFR2, which was necessary for CEC migration. Moreover, sustained activation of Rac1GTP induced by VEGF was eliminated when CECs were transfected with an IQGAP1 construct that is unable to bind Rac1. IQGAP1-mediated Src activation was involved in initiating Rac1 activation, CEC migration, and tube formation. Our findings indicate that CEC IQGAP1 interacts with VEGFR2 to mediate Src activation and subsequent Rac1 activation and CEC migration. In addition, IQGAP1 binding to Rac1GTP results in sustained activation of Rac1, leading to CEC migration toward VEGF. Our study supports a role of IQGAP1 and the interaction between IQGAP1 and Rac1GTP to restore CECs quiescence and, therefore, prevent vision-threatening CNV in nAMD.

Haibo Wang

Aniket Ramshekar

Eric Kunz

David B. Sacks

M. Elizabeth Hartnett

IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation

IQGAP1通过维持VEGFR2介导的Rac1激活导致脉络膜新生血管形成

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies characterized by aberrant and enlarged lymphatic and blood vessels. CLVM appear during fetal development and enlarge after birth, causing life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and disfigurement. Treatment includes surgical debulking, amputation, and recurrent sclerotherapy. Somatic, mosaic mutations in the 110-kD catalytic α-subunit of phosphoinositide-3-kinase (PIK3CA) gene have been previously identified in affected tissues from CLVM patients; however, the cell population harboring the mutation is still unknown. In this study, we hypothesized that endothelial cells (EC) carry the PIK3CA mutations and play a major role in the cellular origin of CLVM. We isolated EC from the lesions of seven patients with CLVM and identified PIK3CA hotspot mutations. The CLVM EC exhibited constitutive phosphorylation of the PI3K effector AKT as well as hyperproliferation and increased resistance to cell death compared to normal EC. Inhibitors of PIK3CA (BYL719) and AKT (ARQ092) attenuated the proliferation of CLVM EC in a dose-dependent manner. A xenograft model of CLVM was developed by injecting patient-derived EC into the flanks of immunocompromised mice. CLVM EC formed lesions with enlarged lymphatic and vascular channels, recapitulating the patient histology. EC subpopulations were further obtained by both immunomagnetic separation into lymphatic EC (LEC) and vascular EC (VEC) and generation of clonal populations. By sequencing these subpopulations, we determined that both LEC and VEC from the same patient express the PIK3CA mutation, exhibit increased AKT activation and can form lymphatic or vascular lesions in mouse.

Timothy D. Le Cras

Jillian Goines

Nora Lakes

Patricia Pastura

Adrienne M. Hammill

Denise M. Adams

Elisa Boscolo

Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation

组成性激活的PIK3CA突变在毛细淋巴静脉畸形中的淋巴管和血管内皮细胞中表达

Abstract Diabetic retinopathy has a high probability of causing visual impairment or blindness throughout the disease progression and is characterized by the growth of new blood vessels in the retina at an advanced, proliferative stage. Microglia are a resident immune population in the central nervous system, known to play a crucial role in regulating retinal angiogenesis in both physiological and pathological conditions, including diabetic retinopathy. Physiologically, they are located close to blood vessels and are essential for forming new blood vessels (neovascularization). In diabetic retinopathy, microglia become widely activated, showing a distinct polarization phenotype that leads to their accumulation around neovascular tufts. These activated microglia induce pathogenic angiogenesis through the secretion of various angiogenic factors and by regulating the status of endothelial cells. Interestingly, some subtypes of microglia simultaneously promote the regression of neovascularization tufts and normal angiogenesis in neovascularization lesions. Modulating the state of microglial activation to ameliorate neovascularization thus appears as a promising potential therapeutic approach for managing diabetic retinopathy. Graphical abstract

Aiyan Hu

Mirko H. H. Schmidt

Nora Heinig

Microglia in retinal angiogenesis and diabetic retinopathy

视网膜血管生成和糖尿病视网膜病变中的小胶质细胞

Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that is known to be inactivated in diabetic subjects. This study aimed to investigate the contribution of PGC-1α inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1α(-/-) mice. Retinal vasculature of PGC-1α(-/-) mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1α(-/-) mice to hyperoxia during retinal vascular development exacerbated these vascular abnormalities, with extensive retinal hemorrhaging and highly unstructured areas as compared with wild-type mice. Structural analysis demonstrated a reduction in membrane-bound VE-cadherin, which was suggestive of defective intercellular junctions. Interestingly, PGC-1α(-/-) retinas showed a constitutive activation of the VEGF-A signaling pathway. This phenotype could be partially reversed by antioxidant administration, indicating that elevated production of ROS in the absence of PGC-1α could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1α control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability.

Nieves García-Quintans

Cristina Sánchez-Ramos

Ignacio Prieto

Alberto Tierrez

Elvira Arza

Arantzazu Alfranca

Juan Miguel Redondo

María Monsalve

Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice

氧化应激导致PGC-1α缺陷小鼠中周细胞覆盖率丧失和血管不稳定性

David M Smadja

Sven Günther

Pauline Cavagna

Bertrand Renaud

Dominique Salmon

Bertrand Hermann

Brigitte Ranque

Cédric Lemogne

Jean-Luc Diehl

Aurélien Philippe

Circulating endothelial cells: a key biomarker of persistent fatigue after hospitalization for COVID-19

循环内皮细胞：COVID-19住院后持续疲劳的关键生物标志物

Abstract Neuropilin-1 (NRP1) regulates endothelial cell (EC) biology through modulation of vascular endothelial growth factor receptor 2 (VEGFR2) signalling by presenting VEGFA to VEGFR2. How NRP1 impacts VEGFA-mediated vascular hyperpermeability has however remained unresolved, described as exerting either a positive or a passive function. Using EC-specific Nrp1 knock-out mice, we discover that EC-expressed NRP1 exerts an organotypic role. In the ear skin, VEGFA/VEGFR2-mediated vascular leakage was increased following loss of EC NRP1, implicating NRP1 in negative regulation of VEGFR2 signalling. In contrast, in the back skin and trachea, loss of EC NRP1 decreased vascular leakage. In accordance, phosphorylation of vascular endothelial (VE)-cadherin was increased in the ear skin but suppressed in the back skin of Nrp1 iECKO mice. NRP1 expressed on perivascular cells has been shown to impact VEGF-mediated VEGFR2 signalling. Importantly, expression of NRP1 on perivascular cells was more abundant in the ear skin than in the back skin. Global loss of NRP1 resulted in suppressed VEGFA-induced vascular leakage in the ear skin, implicating perivascular NRP1 as a juxtacrine co-receptor of VEGFA in this compartment. Altogether, we demonstrate that perivascular NRP1 is an active participant in EC VEGFA/VEGFR2 signalling and acts as an organotypic modifier of EC biology.

Sagnik Pal

Yangyang Su

Emmanuel Nwadozi

Lena Claesson-Welsh

Mark Richards

Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions

神经纤毛蛋白-1通过 juxtacrine 调控内皮粘着连接控制血管通透性

Arteriovenous malformations (AVMs) are abnormal high flow shunts between arteries and veins with major negative impact on the cardiovascular system. Inherited loss-of-function (LOF) mutations in endoglin, encoding an endothelial cell (EC) expressed co-receptor for BMP9/10, causes the disease HHT1/Osler-Weber-Rendu, characterized by bleeding and AVMs. Here we observe increased activity of the downstream signalling complex mTORC1 within the retinal vasculature of HHT mouse models. To investigate its importance in AVM biology, concerning subvascular action, cell specificity, signalling strength and kinetics we combine timed genetic and antibody-based models of HHT with genetic mTORC1 inhibition or activation through EC specific deletion of Rptor or Tsc1. Results demonstrate that EC mTORC1 activation is secondary to endoglin LOF and mainly a consequence of systemic effects following AVM. While genetic EC inhibition of mTORC1 only showed tendencies towards reduced AVM severity, EC overactivation counterintuitively reduced it, implying that mTORC1 must be within a certain range to facilitate AVM. Complete inhibition of mTORC1 signalling by rapamycin provided the strongest therapeutic effect, pointing to potential involvement of RAPTOR-independent pathways or AVM-promoting effects of non-ECs in this pathology.

Antonio Queiro-Palou

Yi Jin

Lars Jakobsson

Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT

遗传和药物靶向小鼠动静脉畸形模型中的mTORC1揭示了HHT中的非细胞自主信号传导

Abstract Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. Aberrations in blood vessel diameter control can cause congenital arteriovenous malformations (AVMs). We show in zebrafish embryos that while arteries behave according to the shear stress set point model, veins do not. This behavior is dependent on distinct arterial and venous endothelial cell (EC) shapes and sizes. We show that arterial ECs enlarge more strongly when experiencing higher flow, as compared to vein cells. Through the generation of chimeric embryos, we discover that this behavior of vein cells depends on the bone morphogenetic protein (BMP) pathway components Endoglin and Alk1. Endoglin ( eng ) or alk1 ( acvrl1 ) mutant vein cells enlarge when in normal hemodynamic environments, while we do not observe a phenotype in either acvrl1 or eng mutant ECs in arteries. We further show that an increase in vein diameters initiates AVMs in eng mutants, secondarily leading to higher flow to arteries. These enlarge in response to higher flow through increasing arterial EC sizes, fueling the AVM. This study thus reveals a mechanism through which BMP signaling limits vein EC size increases in response to flow and provides a framework for our understanding of how a small number of mutant vein cells via flow-mediated secondary effects on wildtype arterial ECs can precipitate larger AVMs in disease conditions, such as hereditary hemorrhagic telangiectasia (HHT).

Zeenat Diwan

Jia Kang

Emma Tsztoo

Arndt F Siekmann

Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues

Alk1/Endoglin信号通路限制静脉细胞在血流动力学提示下的大小增加

Brain arteriovenous malformations (bAVMs) are a major cause of hemorrhagic stroke in children and young adults. These lesions are thought to result from somatic KRAS/BRAF mutations in brain endothelial cells (bECs). In this study, we introduce a new bAVM model by inducing a brain endothelial-specific BrafV600E mutation using the Slc1o1c1(BAC)-CreER driver line. The pathological characteristics of this model resemble human bAVMs, including dilated and hyperpermeable vessels, as well as parenchymal hemorrhage. We observed that these lesions showed a typical reduction in pericyte coverage and disruption of the pericyte-endothelial cell connection. Additionally, we found that ANGPT2 levels were significantly increased in the endothelium of bAVM lesions, which may be a critical factor in the pericyte deficits of the malformed vessels. Treatment with an ANGPT2 neutralizing antibody confirmed that blocking ANGPT2 can restore pericyte density in bAVM lesions, improve pericyte coverage around microvessels, enhance tight junction protein coverage related to endothelial cells, and normalize endothelial barrier function. In summary, our findings suggest that increased ANGPT2 expression in endothelial cells with the BrafV600E mutation is a key factor in pericyte deficiencies in bAVMs, highlighting the potential effectiveness of anti-ANGPT2 therapy in treating bAVMs.

Tianqi Tu

Shikun Zhang

Jingwei Li

Chendan Jiang

Jian Ren

Shiju Zhang

Xiaosheng Meng

Hao Peng

Dong Xing

Hongqi Zhang

Tao Hong

Jiaxing Yu

Inhibition of Angiopoietin-2 rescues sporadic brain arteriovenous malformations by reducing pericyte loss

抑制血管生成素-2通过减少周细胞丢失挽救散发性脑动静脉畸形

Abbreviation
Journal Impact	9.23
Quartiles(Global)	PERIPHERAL VASCULAR DISEASE(Q1)

ISSN	0969-6970, 1573-7209
h-index	101

Publication Information	Publisher: Springer Science and Business Media B.V.，Publishing cycle: Quarterly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2001，Proportion of original research papers: 90.91%，Self Citation Rate:12.00%， Gold OA Rate: 56.48%
Average review cycle	网友分享经验：较慢,6-12周

Angiogenesis

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