Anne Eichmann

Yale University

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Endothelial RAF1/ERK activation regulates arterial morphogenesis

Blood (2013)

Yong Deng Bruno Larrivée Zhen Zhuang Deepak Atri Filipa Moraes

10.1182/blood-2012-12-474601

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Citations (68)

AB002. Guidance of vascular patterning in ocular development and disease

Annals of Eye Science (2018)

Anne Eichmann

Abstract: Ocular vessel networks develop in a highly stereotyped fashion. Abnormal ocular angiogenesis is associated with major diseases including age-related macular degeneration and diabetic retinopathy. Better understanding of mechanisms driving angiogenesis is expected to uncover novel targets to prevent vision loss. Capillary growth is driven by endothelial tip cells, which are selected by dynamic interplay between VEGF, Notch and BMP signaling, with VEGF acting as a positive regulator, and Notch and the BMP receptor Alk1 acting as negative regulators of tip cell formation. The concerted interplay between these molecules ensures that appropriate tip cell numbers leading new vessel branches are formed. In addition, guidance receptors including Neuropilins and Roundabout receptors contribute to vascular patterning by regulating VEGF and BMP signaling. Possibilities to target these pathways during pathological ocular neovascularization will be discussed.

10.21037/aes.2018.ab002

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Cerebral Venous Blood Flow Regulates Brain Fluid Clearance via Meningeal Lymphatics

Research Square (Research Square) (2025)

Marie-Rénée El Kamouh Myriam Spajer Ruchith Singhabahu Kurt A. Sailor Marie‐Charlotte Bourrienne

Abstract The vascular system regulates brain clearance through arterial blood flow and lymphatic drainage of cerebrospinal fluid (CSF). Idiopathic intracranial hypertension (IIH), characterized by elevated intracranial pressure and dural venous sinus stenoses, can be treated by restoring venous blood flow via venous stenting, suggesting a role for venous blood flow in brain fluid clearance. Using magnetic resonance imaging (MRI) in IIH patients and healthy controls, we identified that dural venous stenoses in IIH were associated with impaired lymphatic drainage, perivenous fluid retention, and brain fluid accumulation. To investigate this further, we developed a mouse model with bilateral jugular vein ligation (JVL), which recapitulated key human findings, including intracranial hypertension, calvarial lymphatic regression, and brain swelling due to impaired clearance. To further dissect the respective roles of meningeal lymphatic vessels and venous blood flow in brain clearance, we performed JVL in mice with lymphatic depletion. These mice exhibited spontaneous elevated intracranial pressure, but JVL did not further exacerbate this effect. Moreover, the synchronous restoration of brain clearance and meningeal lymphatics observed in mice after JVL was absent in lymphatic-deficient mice.Transcriptomic analyses revealed that lymphatic remodeling induced by JVL was driven by VEGF-C signaling between dural mesenchymal and lymphatic endothelial cells. These findings establish the dural venous sinuses as a critical platform where venous blood flow interacts with mesenchymal cells to preserve meningeal lymphatic integrity and function, essential for brain fluid clearance.

Glymphatic System

Venous blood

Meninges

Cerebral Spinal Fluid

10.21203/rs.3.rs-5753044/v1

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Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny

Development (1998)

Thierry Jaffredo R. Gautier Anne Eichmann Françoise Dieterlen‐Lièvre

ABSTRACT We have investigated the developmental relationship of the hemopoietic and endothelial lineages in the floor of the chicken aorta, a site of hemopoietic progenitor emergence in the embryo proper. We show that, prior to the onset of hemopoiesis, the aortic endothelium uniformly expresses the endothelium-specific membrane receptor VEGF-R2. The onset of hemopoiesis can be determined by detecting the common leukocyte antigen CD45. VEGF-R2 and CD45 are expressed in complementary fashion, namely the hemopoietic cluster-bearing floor of the aorta is CD45+/VEGF-R2−, while the rest of the aortic endothelium is CD45−/VEGF-R2+. To determine if the hemopoietic clusters are derived from endothelial cells, we tagged the E2 endothelial tree from the inside with low-density lipoproteins (LDL) coupled to DiI. 24 hours later, hemopoietic clusters were labelled by LDL. Since no CD45+ cells were inserted among endothelial cells at the time of vascular labelling, hemopoietic clusters must be concluded to derive from precursors with an endothelial phenotype.

10.1242/dev.125.22.4575

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Citations (579)

Molecular parallels between neural and vascular development

Vascular Pharmacology (2012)

Anne Eichmann

10.1016/j.vph.2011.08.010

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Citations (2)

Conserved meningeal lymphatic drainage circuits in mice and humans

The Journal of Experimental Medicine (2022)

Laurent Jacob José M. Brito Stéphanie Lenck Céline Corcy Farhat Benbelkacem

Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases.

Dural venous sinuses

Glymphatic System

Meninges

Pia mater

10.1084/jem.20220035

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Citations (92)

Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

Nature Communications (2015)

Irene M. Aspalter Emma Gordon Alexandre Dubrac Anan Ragab Jarek Narloch

Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling.

Stalk

Sprouting angiogenesis

10.1038/ncomms8264

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Citations (161)

Molecular Parallels between Neural and Vascular Development

The FASEB Journal (2015)

Anne Eichmann

Anatomical parallels between the nervous and the vascular system are readily apparent in peripheral body tissues, where blood vessels and nerves ramify throughout nearly all domains of the body and are usually aligned. To orchestrate the formation of their highly branched, exquisitely wired networks, nerves and blood vessels have developed shared cellular andmolecular principles. At the cellular level, axons of developing neurons and capillaries use specialized motile structures to ensure their directional guidance. In axons, a growth cone is situated at the axon extremity and ensures axon guidance towards its distant target. In blood vessels, specialized motile endothelial cells (EC) situated at the capillary tips ensure capillary guidance during sprouting angiogenesis. Molecularly, common signaling molecules guide vascular and axonal outgrowth. Axonal growth cones and tip cells express receptors for axon guidance molecules, including Neuropilin receptors (Nrps), Eph family receptor tyrosine kinases, PlexinD1, Robo4 and UNC5B. Loss-of-function of the genes encoding these receptors leads to defects in vessel formation and in most cases to embryonic death, indicating a critical function of axon guidance receptors in vascular development. Their guidance properties and vascular expression makes them attractive targets for approaches directed at inhibiting tumor angiogenesis, or conversely for guiding new vessels towards ischemic tissue areas.

Growth cone

Neuropilin

Axoplasmic transport

Slit

Netrin

10.1096/fasebj.29.1_supplement.75.1

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Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching

Scientific Reports (2024)

Qanber Raza Taliha Nadeem Seock‐Won Youn Bhairavi Swaminathan Ahana Gupta

Abstract Notch signaling guides vascular development and function by regulating diverse endothelial cell behaviors, including migration, proliferation, vascular density, endothelial junctions, and polarization in response to flow. Notch proteins form transcriptional activation complexes that regulate endothelial gene expression, but few of the downstream effectors that enable these phenotypic changes have been characterized in endothelial cells, limiting our understanding of vascular Notch activities. Using an unbiased screen of translated mRNA rapidly regulated by Notch signaling, we identified novel in vivo targets of Notch signaling in neonatal mouse brain endothelium, including UNC5B , a member of the netrin family of angiogenic-regulatory receptors. Endothelial Notch signaling rapidly upregulates UNC5B in multiple endothelial cell types. Loss or gain of UNC5B recapitulated specific Notch-regulated phenotypes. UNC5B expression inhibited endothelial migration and proliferation and was required for stabilization of endothelial junctions in response to shear stress. Loss of UNC5B partially or wholly blocked the ability of Notch activation to regulate these endothelial cell behaviors. In the developing mouse retina, endothelial-specific loss of UNC5B led to excessive vascularization, including increased vascular outgrowth, density, and branchpoint count. These data indicate that Notch signaling upregulates UNC5B as an effector protein to control specific endothelial cell behaviors and inhibit angiogenic growth.

Hes3 signaling axis

10.1038/s41598-024-64375-z

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Endothelial ERK signaling controls lymphatic fate specification

Journal of Clinical Investigation (2013)

Yong Deng Deepak Atri Anne Eichmann Michael Simons

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1S259A) that is associated with Noonan syndrome. Expression of mutant RAF1S259A in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate. Excessive production of lymphatic ECs resulted in lymphangiectasia that was highly reminiscent of abnormal lymphatics seen in Noonan syndrome and similar "RASopathies." Inhibition of ERK signaling during development abrogated the lymphatic differentiation program and rescued the lymphatic phenotypes induced by expression of RAF1S259A. These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases.

Noonan Syndrome

Lymphatic Endothelium

Lymphatic vessel

10.1172/jci63034

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Citations (126)