Papers in Vascular Biology Accordions
With the help of experts in each discipline, we have identified papers that we believe to be fundamental in the field of vascular biology. You can search by keywords or authors (last name is sufficient). If your keyword appears in the list of tags or in the title of the paper, it will be included in your search results. For additional instructions, click on the gray bar.
- Blood Vessel Development
- Heart Development
- Lymphatic Vessel Development
- Blood Vessels Cell
- Vasomotor Response
- Blood Cell Interactions
- Lymphatic Vessels
- In Silico Modeling
|ACSL1||Coronary Vessel Development||INSR||Podoplanin|
|Acyl-CoA Synthetase 1||Coronary Vessels||Insulin Signaling||Proteoglycans|
|Alk1||Deep Cervical Lymph Nodes||JAM-C||RBP-J|
|Aorta||Diabetic Atherosclerosis||KLF4 Chip-Seq||Repulsion|
|Apelin Receptor||Dietary Choline||Knockout||Resistance|
|APJ||Differentiation||Knockout Mouse||Retinopathy choroid|
|APLNR||Dll4||L-1B Lineage Tracing||Reverse Genetic Screening|
|Apoptosis||DNA Microarrays||Layers||Rouget cells|
|Arterial Endothelial Cell||Dosage Sensitivity||LDLR Cytokines||Runx1|
|Arterial neural bundles||Dural Sinus||Lectins||S100A8|
|Arterial Pressure||EGF||Lesion Pathogenesis||S100A9|
|Arterial Smooth Muscle||Elastase||Leukocyte Rolling||Selectins|
|Arteriole||Endocardial Cells||Loeys-Dietz syndrome||Signaling|
|Arteriovenous||Endothelial Cell Differentiation||Ly6G+ Cells||Simulation|
|Arteriovenous Fate||Endothelial Cell Diversity||Lymph Node||Simulation|
|Arteriovenous Malformation||Endothelial Cell Fate||Lymph Node-Resident||Sinus Venosus|
|Arteriovenous Specification||Endothelial Cell Identity||Lymphatic Endothelial Cells||SMC Progenitors|
|Arteriovenous Specification A||Endothelial junction||Lymph Nodes||Smooth muscle|
|Artery||Endothelium||Lymphangiogenesis||Smooth Muscle Cell|
|Artiorgenic remodeling||eNOS||Lymphatic Cell Differentiation||Specification|
|Atheroprotected||EphrinB2||Lymphatic Endothelial Cell||Stem cells|
|Atheroprotected ER stress||Epicardium||Lymphatic Specification||Stroke|
|Atherosclerosis||ER Stress||Lymphatic Vessels||TGF-B Signaling|
|Atherosclerotic Plaques||Extracellular Matrix||Lymphvasculogenesis||Thrombosis|
|Atherosusceptible||Extracellular Matrix Proteins||Macrophage||Thrombotic event|
|Autoregulation||Eye||Macular degeneration||Thrombotic Events|
|Blood Circulation||Fibrosis||Matrix Metalloproteases||Tip cell|
|Blood Flow||Fibrous Cap||Mechanosensory Complex||Tissue specificity|
|Blood Pressure||Fluid Flow||Mechanotransduction||TMAO|
|Blood vessel||Foam Cells||Mesenchymal Stem Cell||Transcription|
|Bone marrow||Fusion||Mesenteric Lymphatic Vessels||Transendothelial migration|
|Bradycardia||Gap Junction||Microvascular Endothelial Cells||Transgenic|
|CANTOS Trial||Gene Expression||Morphogenesis||Trimethylamine N-Oxide|
|Cardiac Progenitor Cells||Genetics||Mouse||Type 1 Diabetes|
|Cardiac Regeneration||Glucose||Mural cells||Ultrasonic|
|Cardiovascular disease||Glycans||Myelopoiesis||Vascular diseases|
|Cat||Gridlock||Myocardial Infarct||Vascular Permeability|
|Cat||Growth factors||Myocardium||Vascular Remodeling|
|Caveolae||Guidance||Myofibroblast||Vascular Smooth Muscle|
|Caveolin-1||Gut Microbiome||Negative regulators||Vascular System|
|CD8 T Cell||Haploinsufficiency||Neutrophil||Vasculogenesis|
|Cell Junction||Heart||Nitric Oxide||Vasodilation|
|Cell Senescence||Hemodynamics||Notch||Vasodilator Agents|
|Cell Structure||Hemogenic Endothelial Cells||Pattern formation||Vasomotor System|
|Cell turnover||Hemorrhage||PD-1 Ligand 1||VE-Cadherion|
|Central Nervous System||Hereditary Hemorrhagic Telangiectasia||PDGF||VEGF|
|Cerebrospinal Fluid||Heterotypic adhesion||PDGF-B||VEGF-C|
|Chemokines||High Endothelial Venules||PDGFR||VEGFR2|
|Chick-Quail Chimera||Hindlimb ischemia||Pericyte||Vein|
|Cholesterol||Histamine||Peripheral Immune Tolerance||Venule|
|Cholinergic||Hyaluronan||Peripheral Tissue Antigen||Venules|
|Circulating endothelial cells||Hypertension||PI3K||Vesicles|
|CLEC-2||Hypotension||Platelet Activation||Vessel Wall|
|Collaterals||Immune Cells||Platelets||Wall Mechanics|
Here is a listing of electronic publications authored by NAVBO members and of relevance to the entire Vascular Biology Community.
Bin Liu, Yi Peng, Dan Yi, Narsa Machireddy, Daoyin Dong, Karina Ramirez, Jingbo Dai, Rebecca Vanderpool, Maggie M Zhu, Zhiyu Dai, You-Yang Zhao
Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model [Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 (PHD2)] with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) or endothelial Nos3 knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/gRNA plasmid DNA inhibited obliterative pulmonary vascular remodeling and attenuated severe PH in Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PH and improved right heart function. These data suggest that suppression of Caveolin-1 expression secondary to PHD2 deficiency augments nitrative stress through eNOS activation, which contributes to obliterative vascular remodeling and severe PH. Thus, reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.
Eur Respir J. 2022 Jul 7;2102643. doi: 10.1183/13993003.02643-2021. Online ahead of print.
Andrea J Radtke, Jessica M Lukacs, Nancy E Praskievicz, Selen C Muratoglu, Ilsa I Rovira, Zorina S Galis.
Nature Medicine. 2022 Jun 9. doi: 10.1038/s41591-022-01865-5. Online ahead of print.
Lars J Jensen, Morten A V Lund, Max Salomonsson, Jens Peter Goetze, Thomas E Jonassen, Niels-Henrik Holstein-Rathlou, Lene N Axelsen, Charlotte M Sørensen
The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na+ excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14 weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses.
Microvasc Res. 2022 Feb 10;104333. doi: 10.1016/j.mvr.2022.104333. Online ahead of print.
Amirali Selahi, Teshan Fernando, Sanjukta Chakraborty, Mariappan Muthuchamy, David C Zawieja, Abhishek Jain
The pathophysiology of several lymphatic diseases, such as lymphedema, depends on the function of lymphangions that drive lymph flow. Even though the signaling between the two main cellular components of a lymphangion, endothelial cells (LECs) and muscle cells (LMCs), is responsible for crucial lymphatic functions, there are no in vitro models that have included both cell types. Here, a fabrication technique (gravitational lumen patterning or GLP) is developed to create a lymphangion-chip. This organ-on-chip consists of co-culture of a monolayer of endothelial lumen surrounded by multiple and uniformly thick layers of muscle cells. The platform allows construction of a wide range of luminal diameters and muscular layer thicknesses, thus providing a toolbox to create variable anatomy. In this device, lymphatic muscle cells align circumferentially while endothelial cells aligned axially under flow, as only observed in vivo in the past. This system successfully characterizes the dynamics of cell size, density, growth, alignment, and intercellular gap due to co-culture and shear. Finally, exposure to pro-inflammatory cytokines reveals that the device could facilitate the regulation of endothelial barrier function through the lymphatic muscle cells. Therefore, this bioengineered platform is suitable for use in preclinical research of lymphatic and blood mechanobiology, inflammation, and translational outcomes.
Lab Chip. 2021 Dec 21;22(1):121-135. doi: 10.1039/d1lc00720c.
Development of the mammalian lymphatic vasculature is a stepwise process requiring the specification of lymphatic endothelial cell progenitors in the embryonic veins, and their subsequent budding to give rise to most of the mature lymphatic vasculature. In mice, formation of the lymphatic vascular network starts inside the cardinal vein at around E9.5 when a subpopulation of venous endothelial cells gets committed into the lymphatic lineage by their acquisition of Prox1 expression. Identification of critical genes regulating lymphatic development facilitated the detailed cellular and molecular characterization of some of the cellular and molecular mechanisms regulating the early steps leading to the formation of the mammalian lymphatic vasculature. A better understanding of basic aspects of early lymphatic development, and the availability of novel tools and animal models has been instrumental in the identification of important novel functional roles of this vasculature network.
Developmental Biology, Volume 482, February 2022, Pages 44-54
Michael T. Yarboro, Srirupa H. Gopal, Rachel L. Su, Thomas M. Morgan, Jeff Reese.
The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
Dev Dynam., 2021 Aug 4. doi: 10.1002/dvdy.408. Online ahead of print.
Sonali S. Shaligram, Rui Zhang, Wan Zhu, Li Ma, Man Luo, Qiang Li, Miriam Weiss, Thomas Arnold, Nicolas Santander, Rich Liang, Leandro do Prado, Chaoliang Tang, Felix Pan, S. Paul Oh, Peipei Pan & Hua Su
We have previously demonstrated that deletion of activin receptor-like kinase 1 (Alk1) or endoglin in a fraction of endothelial cells (ECs) induces brain arteriovenous malformations (bAVMs) in adult mice upon angiogenic stimulation. Here, we addressed three related questions: (1) could Alk1− mutant bone marrow (BM)-derived ECs (BMDECs) cause bAVMs? (2) is Alk1− ECs clonally expended during bAVM development? and (3) is the number of mutant ECs correlates to bAVM severity? For the first question, we transplanted BM from PdgfbiCreER;Alk12f/2f mice (EC-specific tamoxifen-inducible Cre with Alk1-floxed alleles) into wild-type mice, and then induced bAVMs by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor and intra-peritoneal injection of tamoxifen. For the second question, clonal expansion was analyzed using PdgfbiCreER;Alk12f/2f;confetti+/− mice. For the third question, we titrated tamoxifen to limit Alk1 deletion and compared the severity of bAVM in mice treated with low and high tamoxifen doses. We found that wild-type mice with PdgfbiCreER;Alk12f/2f BM developed bAVMs upon VEGF stimulation and Alk1 gene deletion in BMDECs. We also observed clusters of ECs expressing the same confetti color within bAVMs and significant proliferation of Alk1− ECs at early stage of bAVM development, suggesting that Alk1− ECs clonally expanded by local proliferation. Tamoxifen dose titration revealed a direct correlation between the number of Alk1− ECs and the burden of dysplastic vessels in bAVMs. These results provide novel insights for the understanding of the mechanism by which a small fraction of Alk1 or endoglin mutant ECs contribute to development of bAVMs.
Transl Stroke Res. 2021 Oct 21. doi: 10.1007/s12975-021-00955-9. Online ahead of print.
Osama F Harraz, Lars Jørn Jensen
Changes in cellular Ca2+ levels have major influences on vascular function and blood pressure regulation. Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) orchestrate vascular activity in distinct ways, often involving highly-specific fluctuations in Ca2+ signaling. Aging is a major risk factor for cardiovascular diseases, but the impact of aging per se on vascular Ca2+ signaling has received insufficient attention. We reviewed the literature for age-related changes in Ca2+ signaling in relation to vascular structure and function. Vascular tone dysregulation in several vascular beds has been linked to abnormal expression or activity of SMC voltage-gated Ca2+ channels, Ca2+ -activated K+ channels or TRPC6 channels. Some of these effects were linked to altered caveolae density, microRNA expression, or 20-HETE abundance. Intracellular store Ca2+ handling was suppressed in aging mainly via reduced expression of intracellular Ca2+ release channels, and Ca2+ reuptake or efflux pumps. An increase in mitochondrial Ca2+ uptake, leading to oxidative stress, could also play a role in SMC hypercontractility and structural remodeling in aging. In ECs, aging entailed diverse effects on spontaneous and evoked Ca2+ transients, as well as structural changes at the EC-SMC interface. The concerted effects of altered Ca2+ signaling on myogenic tone, endothelium-dependent vasodilatation, and vascular structure are likely to contribute to blood pressure dysregulation and blood flow distribution deficits in critical organs. With the rise in the world aging population, future studies should be directed at solving specific aging-induced Ca2+ signaling deficits to combat the imminent accelerated vascular aging and increased risk of cardiovascular diseases. Abstract figure: Aging is often associated with a change in vascular function. Resistance vessels-that control peripheral resistance, and therefore blood pressure-demonstrate altered vascular tone and impaired vascular conduction. These changes can be traced back to defective Ca2+ signaling in the building blocks of resistance vessels, smooth muscle cells (SMC) and endothelial cells (EC). Alterations in the activity of ion channels that permeate or respond to Ca2+ signals, intracellular handling of Ca2+ and mitochondrial dysfunction have been implicated in aging-associated vascular dysfunction. This article is protected by copyright. All rights reserved.
J Physiol., 2021 Oct 27. doi: 10.1113/JP280950.Online ahead of print.
Arin K. Greene, Pascal Brouillard, Christopher L. Sudduth, Patrick J. Smits, Dennis J. Konczyk, Miikka Vikkula
Primary lymphedema results from the anomalous development of the lymphatic system and typically presents during infancy, childhood, or adolescence. Adult-onset primary lymphedema is rare and mutations associated with this condition have not been identified. The purpose of this investigation was to search for variants that cause adult-onset primary lymphedema. We discovered an autosomal dominant EPHB4 mutation in a patient who developed unilateral leg lymphedema at age 39 years; the same mutation affected his son who presented with the disease at 14 years of age.
Am J Med Genet A, 2021 Jul 7. doi: 10.1002/ajmg.a.62416. Online ahead of print.
Ariel Alejandro Szklanny, Majd Machour, Idan Redenski, Václav Chochola, Idit Goldfracht, Ben Kaplan, Mark Epshtein, Haneen Simaan Yameen, Uri Merdler, Adam W. Feinberg, Dror Seliktar, Netanel Korin. Josef Jaroš, Shulamit Levenberg
Engineering hierarchical vasculatures is critical for creating implantable functional thick tissues. Current approaches focus on fabricating mesoscale vessels for implantation or hierarchical microvascular in vitro models, but a combined approach is yet to be achieved to create engineered tissue flaps. Here, millimetric vessel-like scaffolds and 3D bioprinted vascularized tissues interconnect, creating fully engineered hierarchical vascular constructs for implantation. Endothelial and support cells spontaneously form microvascular networks in bioprinted tissues using a human collagen bioink. Sacrificial molds are used to create polymeric vessel-like scaffolds and endothelial cells seeded in their lumen form native-like endothelia. Assembling endothelialized scaffolds within vascularizing hydrogels incites the bioprinted vasculature and endothelium to cooperatively create vessels, enabling tissue perfusion through the scaffold lumen. Using a cuffing microsurgery approach, the engineered tissue is directly anastomosed with a rat femoral artery, promoting a rich host vasculature within the implanted tissue. After two weeks in vivo, contrast microcomputer tomography imaging and lectin perfusion of explanted engineered tissues verify the host ingrowth vasculature's functionality. Furthermore, the hierarchical vessel network (VesselNet) supports in vitro functionality of cardiomyocytes. Finally, the proposed approach is expanded to mimic complex structures with native-like millimetric vessels. This work presents a novel strategy aiming to create fully-engineered patient-specific thick tissue flaps.
Adv Mater. 2021 Sep 12;e2102661. doi: 10.1002/adma.202102661. Online ahead of print.
Patterson EK, Gillio-Meina C, Martin CM, Fraser DD, Van Nynatten LR, Slessarev M, Cepinskas G.
In sepsis-induced inflammation, polymorphonuclear neutrophils (PMNs) contribute to vascular dysfunction. The serine proteases proteinase 3 (PR3) and human leukocyte elastase (HLE) are abundant in PMNs and are released upon degranulation. While HLE's role in inflammation-induced endothelial dysfunction is well studied, PR3's role is largely uninvestigated. We hypothesized that PR3, similarly to HLE, contributes to vascular barrier dysfunction in sepsis. Plasma PR3 and HLE concentrations and their leukocyte mRNA levels were measured by ELISA and qPCR, respectively, in sepsis patients and controls. Exogenous PR3 or HLE was applied to human umbilical vein endothelial cells (HUVECs) and HUVEC dysfunction was assessed by FITC-dextran permeability and electrical resistance. Both PR3 and HLE protein and mRNA levels were significantly increased in sepsis patients (P < 0.0001 and P < 0.05, respectively). Additionally, each enzyme independently increased HUVEC monolayer FITC-dextran permeability (P < 0.01), and decreased electrical resistance in a time- and dose-dependent manner (P < 0.001), an effect that could be ameliorated by novel treatment with carbon monoxide-releasing molecule 3 (CORM-3). The serine protease PR3, in addition to HLE, lead to vascular dysfunction and increased endothelial permeability, a hallmark pathological consequence of sepsis-induced inflammation. CORMs may offer a new strategy to reduce serine protease-induced vascular dysfunction.
Exp Biol Med (Maywood) . 2021 Jul 22;15353702211029284. doi: 10.1177/15353702211029284. Online ahead of print.
Peipei Pan, Shantel Weinsheimer, Daniel Cooke, Ethan Winkler, Adib Abla, Helen Kim, Hua Su
Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase (MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.
J Cereb Blood Flow Metab. 2021 Jun 23;271678X211026771. doi: 10.1177/0271678X211026771. Online ahead of print.
Delayna Paulson, Rebecca Harms, Cody Ward, Mackenzie Latterell, Gregory J. Pazour, and Darci M. Fink
Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells in vitro and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels in vivo. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.
Front. Cell Dev. Biol., 14 May 2021 | https://doi.org/10.3389/fcell.2021.672625.
Caitlin R Francis, Shea Claflin, Erich J Kushner
Objective: Vascular lumen formation requires the redistribution of intracellular proteins to instruct apicobasal polarity, thereby enforcing maturation of both luminal and basal domains. In the absence of proper apical signaling, lumen formation can be distorted leading to lumen collapse and cessation of blood flow. Slp2a (synaptotagmin-like protein-2a) has been implicated in apical membrane signaling; however, the role of Slp2a in vascular lumen formation has never been assessed. Approach and Results: Our results demonstrate that Slp2a is required for vascular lumen formation. Using a 3-dimensional sprouting assay, sub-cellular imaging, and zebrafish blood vessel development, we establish that Slp2a resides at the apical membrane acting as a tether for Rab27a that decorates Weibel-Palade bodies (WPBs). We show that Slp2a regulates exocytic activity of WPBs, thus regulating release of WPB contents into the luminal space during angiogenesis. Angiopoietin-2 is a Tie-2 receptor ligand that is selectively released from WPB secretory granules. We identify a critical role for angiopoietin-2 in regulating endothelial lumenization and show that in the absence of Slp2a, WPB contents cannot fuse with the apical membrane. This disrupts the release of angiopoietin-2 and blocks Tie-2 signaling necessary for proper lumen formation.
Conclusions: Our results demonstrate a novel requirement of Slp2a for vascular lumen formation. Moreover, we show that Slp2a is required for the exocytic release of WPB secretory granule cargo during vascular lumen development, and thus is a core upstream component of the WPB secretory pathway. Furthermore, we provide evidence that WPB-housed angiopoietin-2 is required for vascular lumen formation.
Arterioscler Thromb Vasc Biol. 2021 Apr 15;ATVBAHA121316113. doi: 10.1161/ATVBAHA.121.316113. Online ahead of print.
Daniyal J Jafree, David A Long, Peter J Scambler, Christiana Ruhrberg
Lymphatic vessels have critical roles in both health and disease and their study is a rapidly evolving area of vascular biology. The consensus on how the first lymphatic vessels arise in the developing embryo has recently shifted. Originally, they were thought to solely derive by sprouting from veins. Since then, several studies have uncovered novel cellular mechanisms and a diversity of contributing cell lineages in the formation of organ lymphatic vasculature. Here, we review the key mechanisms and cell lineages contributing to lymphatic development, discuss the advantages and limitations of experimental techniques used for their study and highlight remaining knowledge gaps that require urgent attention. Emerging technologies should accelerate our understanding of how lymphatic vessels develop normally and how they contribute to disease.
Angiogenesis. 2021 Apr 6. doi: 10.1007/s10456-021-09784-8. Online ahead of print.
Giovanni Canu, Christiana Ruhrberg
Hematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.
Angiogenesis. 2021 Mar 30. doi: 10.1007/s10456-021-09783-9. Online ahead of print.
David R Hootnick, E Mark Levinsohn
The congenitally shortened limb (CSL) with fibular deficiency or absence has historically been graded by plain radiography, while associated cartilaginous and arterial soft tissue anomalies have been comparatively neglected. Consistent pathological evidence of remnant cartilaginous bodies in place of the fibula presupposes earlier existence of a preformed cartilaginous template of the fibula. In complete fibular radiographic absences, often associated with midline metatarsal deficiencies, the two usual nutrient arteries to the fibula fail to form, as they normally would have, around the (16–18 mm stage) sixth embryonic week. The histopathology of fallow persisting fibular anlagen, in association with missing arteries and retained primitive arteries, suggests the anlage is a dystrophic, but otherwise normally prefigured, cartilaginous scaffold of the fibula. Thus, the widely employed term absent fibula, which has been grounded in plain radiography, is a misnomer. Additionally, since the metatarsals missing in congenitally shortened limb are midline, the related term, fibular hemimelia, is similarly inaccurate. A new taxonomy, based on embryological principles rather than radiographic appearance alone, will promote limb dystrophism as a more accurate term combining arrested embryonic vascular development and congenitally shortened limb of the lower extremity.
Anat Rec (Hoboken. 2021 Mar 26. doi: 10.1002/ar.24628. Online ahead of print.
Ntokou A, Dave JM, Kauffman AC, Sauler M, Ryu C, Hwa J, Herzog EL, Singh I, Saltzman WM, Greif DM
Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor (PDGF)-B induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA is upregulated in mice, and LysM Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, 2a, or Pdgfb have reduced macrophage Pdgfb and are protected against distal muscularization and PH. Conversely, LysM Cre, von-Hippel Lindau(flox/flox) mice have increased macrophage Hifa and Pdgfb and develop distal muscularization, PH and RVH in normoxia. Similarly, Pdgfb is upregulated in macrophages from human idiopathic or systemic sclerosis-induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increases SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduces lung macrophage Pdgfb and prevents hypoxia-induced distal muscularization, PH and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.
JCI Insight. 2021 Feb 16;139067. doi: 10.1172/jci.insight.139067. Online ahead of print.