Biochemical and mechanical signals in the lymphatic vasculature

Geng, Xin; Ho, Yen‐Chun; Srinivasan, Ramesh

doi:10.1007/s00018-021-03886-8

Cited by 16 publications

(23 citation statements)

References 234 publications

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“…The lymphatic system is an important defense system of the human body, closely related to the cardiovascular system, and plays a significant role in the distribution of fluids and nutrients in the body. , When we accurately injected quantitative dual-Pdots (12 μL, 300 μg/mL) into the inguinal lymph nodes, not only the outlines of the main lymphatic vessels and the branches of the lymphatic vessels were clearly monitored (Figure a) but also the shape of the lymphatic valves was clearly visible simultaneously (Figure b) with a stereomicroscope. Moreover, we measured the size of the lymphatic vessels and their branches to be 86.15 and 74.65 μm, respectively (Figure f).…”

Section: Resultsmentioning

confidence: 99%

Multifunctional Imaging of Vessels, Brown Adipose Tissue, and Bones in the Visible and Second Near-infrared Region Using Dual-Emitting Polymer Dots

Zhang

et al. 2022

ACS Appl. Mater. Interfaces

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Dual-emitting polymer dots (dual-Pdots) in the visible and second near-infrared (NIR-II) region can facilitate the high-resolution imaging of the fine structure and improve the signal-to-noise ratio in in vivo imaging. Herein, combining high brightness of Pdots and multi-scale imaging, we synthesized dual-Pdots using a simple nano-coprecipitation method and performed multi-functional imaging of vessels, brown adipose tissue, and bones. Results showed that in vivo blood vessel imaging had a high resolution of up to 5.9 μm and bone imaging had a signal-to-noise ratio of 3.9. Moreover, dual-Pdots can accumulate in the interscapular brown adipose tissue within 2 min with a signal-to-noise ratio of 5.8. In addition, the prepared dual-Pdots can image the lymphatic valves and the frequency of contraction. Our study provides a feasible method of using Pdots as nanoprobes for multi-scale imaging in the fields of metabolic disorders, skeletal system diseases, and circulatory systems.

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Section: Resultsmentioning

confidence: 99%

Multifunctional Imaging of Vessels, Brown Adipose Tissue, and Bones in the Visible and Second Near-infrared Region Using Dual-Emitting Polymer Dots

Zhang

et al. 2022

ACS Appl. Mater. Interfaces

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“…Several mechanosensing molecules have been associated with endothelial mechanotransduction, including Piezo1/2, integrins, PECAM1 (platelet and endothelial cell adhesion molecule 1), KDR (kinase insert domain receptor), and CDH5 (cadherin 5). 3 Among them, as mutations in Piezo1 have been reported to cause an autosomal recessive generalized lymphatic dysplasia, 29,30 we chose to investigate Piezo1 as the top candidate molecule that may ask whether activation of Piezo1 would enhance lymphangiogenesis and prevent surgery-associated lymphedema formation using a mouse lymphedema model. Indeed, Yoda1 was found to effectively prevent tissue swelling and associated fibrosis through enhanced lymphatic growth, indicating a therapeutic potency of Yoda1 against surgeryassociated lymphedemas.…”

Section: Discussionmentioning

confidence: 99%

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion

Choi

Park

et al. 2022

Circulation Research

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Background: Mutations in PIEZO1 cause human lymphatic malformations. We have previously uncovered an Orai1-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. Methods: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. Results: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as Klf2 , Dtx1 , Dtx3L , and Notch1 , which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. Conclusions: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

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“…Structural differences across the vascular hierarchy also influence mechanical signaling in the tissue microenvironment as fluid moves through and around lymphatic vasculature. Mechanosensitive molecules and intracellular mechanotransduction signaling pathways that are activated by mechanical inputs are responsible for how LECs and stromal cells sense and respond to these dynamic changes (Reviewed by Geng et al., 2021 [ 95 ] ). Lymphatic capillaries primarily experience transmural flow across the vessel wall via their discontinuous button‐like junctions, which differs from higher magnitude laminar flow, luminal shear, oscillatory shear, and interstitial pressure experienced by LECs in larger collecting vessels (Figure 1).…”

Section: Mechanoregulation In Lymphatic Vasculaturementioning

confidence: 99%

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Ruliffson

Whittington

2023

Advanced Biology

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Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis‐related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis‐related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease—enabled through more accurate preclinical modeling—will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients.

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Biochemical and mechanical signals in the lymphatic vasculature

Cited by 16 publications

References 234 publications

Multifunctional Imaging of Vessels, Brown Adipose Tissue, and Bones in the Visible and Second Near-infrared Region Using Dual-Emitting Polymer Dots

Multifunctional Imaging of Vessels, Brown Adipose Tissue, and Bones in the Visible and Second Near-infrared Region Using Dual-Emitting Polymer Dots

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

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