Neuropilins: Healthy blood vessels, lymphedema, Covid brain

Key takeaways:
~ Neuropilins (NRPs) are cell receptors that have several roles, including in promoting the growth of blood vessels and lymph vessels.
~ Variants in the neuropilin (NRP) genes are linked to lymphedema and heart disease.
~ NRP1 and NRP2 are receptors for SARS-CoV-2.
~ NRPs are located in the endothelium, on neurons, and on immune system cells — all key locations linked to symptoms experienced after exposure to the SARS-CoV-2 spike protein.

In this article, I’ll cover background information on these receptors, along with genetic variants that impact their function. Members will see their genotype report below, plus additional solutions in the Lifehacks section. Join today 

What is neuropilin 1 and 2?

Neuropilins are glycoproteins, which means structurally, they contain a protein combined with a carbohydrate group. Neuropilins act as receptors and are found on the surface of cells, including on neurons and epithelial cells. They were originally identified for their role in guiding axons to the right place during brain development. Since then, researchers have discovered many roles for neuropilins.[ref]

NRP1 and NRP2 are the main regulators of blood and lymphatic vessel growth. They can also bind the hepatocyte growth factor.[ref]

Neuropilin Functions:

  • Promote the growth of blood vessels
  • Play a role in immune cells
  • Can help with neuronal remyelination
  • Affects the lymphatic system
  • May increase the survival of cancer cells
  • Acts as a SARS-CoV-2 spike protein receptor

There are two types of neuropilin, appropriately called neuropilin 1 and neuropilin 2.

Neuropilin 1 and 2 both act as a co-receptor for VEGF (vascular endothelial growth factor) as well as other growth factors.

  • Neuropilin 1 (NRP1) promotes the growth of blood vessels
  • Neuropilin 2 (NRP2) promotes the growth of lymph vessels.

Additionally, neuropilins 1 and 2 act as co-receptors with semaphorins, which are involved in the development and growth of neurons and other tissues. Semaphorins also interact with the neuropilin receptors in the immune system.[ref]

Animal studies show neuropilin 1 (NRP1) is essential for fetal development. Without the NRP1 gene, mice die in utero. On the other hand, too much NRP1 is also lethal, with excessive capillaries, hemorrhaging, and nervous system defects. Neuropilin 2 (NRP2) is not essential for life, but without NRP2, mice have impaired brain formation and smaller lymphatic vessels.[ref]

Let’s look at these roles in more detail:

Lymphedema:

Rare mutations in the NRP1 and NRP2 genes are linked to increased susceptibility to lymphedema, which is swelling due to the accumulation of lymph fluid in the legs or arms.

While VEGF (vascular endothelial growth factor) is best known for its role in promoting the growth of blood vessels, two types of VEGF, BEGF-C and VEGF-D, are important in the development of the lymphatic system.

NRP1 is involved in the lymphatic valves, and NRP2 is important in lymphatic vessel growth.[ref] Changes to the lymphatic system can result in lymphedema due to the lymph fluid leaking out of the lymph vessels instead of circulating normally.

Neuropilin in SARS-CoV-2:

Neuropilin 1 (NRP1) has been identified in a bunch of studies as being a receptor for SARS-CoV-2. While much focus was on ACE2, which was identified early on as the entry mechanism for both SARS and SARS-CoV-2, it turns out that several other cell receptors (including NRP1) can be a co-receptor that binds to the spike protein.[ref][ref][ref]

While the spike protein can bind to NRPs, the ACE2 receptor binding is about twice as efficient. Thus, most research has focused on ACE2. However, the NRP receptor binding may be important in the neurological symptoms and loss of smell in people with SARS-CoV-2 infections.[ref]

When doctors examine post-mortem brain tissue, they have found the presence of some of the SARS-CoV-2 viral particles in brain capillaries and neurons. One possible entry route is NRP1. Analyses show that NRP1 is upregulated in COVID-19 patients. The ACE2 receptor is not usually found in neurons, so researchers think that the spike protein binding to NRP1 may be important in neurological symptoms after Covid.[ref] (and perhaps long Spike?).

Viral entry for other viruses:

In addition to SARS-Co-V-2, the neuropilins are also involved in viral entry for several other viruses. For example, NRP1 is a receptor for Epstein-Barr Virus, Human T-cell Lymphotropic virus type 1, and enterovirus 71. NRP2 is a receptor for cytomegalovirus.[ref]

Neuropilins in the immune system:

In immune system cells, neuropilin 1 and 2 are found in regulatory T cells, macrophages, thymocytes, and dendritic cells. Researchers are still trying to figure out exactly what role neuropilins play in these immune cells.[ref]

New research also points to neuropilin 1 as a receptor for complement split products (CSPs). The complement system is part of the immune system, acting to increase the ability of other immune cells to clear out pathogens and damaged cells. CSP fragments of C4 and C3 were found to bind with NRP1.[ref]

Neuropilin 1 in vascular permeability:

The endothelium is the single layer of cells lining the blood vessels. It is more than just a lining, though, the endothelium also regulates how molecules, such as nutrients and oxygen, come in and out of the bloodstream. It is a ‘selective barrier’ that can adapt to different tissues and different localized needs.

Vascular permeability is the term applied to how open the endothelium is to allowing plasma, etc., out of the blood vessels. In certain diseases, vascular hyperpermeability can cause edema and swelling.

Neuropilin 1 (NRP1) is found throughout the endothelium. In addition to its role in blood vessel formation, recent research shows that NRP1 is also important in promoting vascular permeability. Currently, researchers are looking at targeting NRP1 with drugs in diseases such as diabetic retinopathy to prevent edema in the eye.[ref]

Mast Cells and neuropilins:

Mast cells are immune system cells best known for giving off a lot of histamines when exposed to an allergen. However, mast cells do more than just make your nose run and eyes water during pollen season. They are immune system sentinels found in the skin, respiratory tract, gastrointestinal tract, and heart. When encountering pathogens, allergens, cytokines, or other chemical triggers, mast cells degranulate and release inflammatory molecules, including histamine and tryptase.

Mast cells express the NRP1 and NRP2 receptors, along with the co-receptors for VEGF (vascular endothelial growth factors).[ref] Mast cells can also release VEGF when stimulated. A recent study found that people with mastocytosis, a disease that causes excessive mast cell activation, have higher levels of VEGF when symptomatic. It correlates to higher levels of vascular permeability and endothelial dysfunction.[ref]

NRP1 in menstrual migraines:

A large genome-wide association study looked for genetic variants related to menstrual migraines. A surprising finding was that a variant in NRP1 (neuropilin 1) was the strongest link to menstrual migraines. It differed from other migraine genome-wide studies, adding to the evidence that the vascular system is involved in migraines for some people. Neuropilin 1 is also involved in the vascular repair of the endometrium in the menstrual cycle.[ref]

Cancer growth and neuropilins:

Tumors grow quickly and need blood vessels to supply them with more nutrients. Thus, reducing the growth of blood vessels into a tumor is one way to cut off growth. Currently, there is a lot of research into how targeting neuropilins can help to decrease blood vessel growth in cancer. Additionally, neuropilins play a role in how cells migrate in several types of tissues. Thus, targeting neuropilins may help to decrease metastasis in cancers.[ref]

Semaphorins and NRP1/2:

Semaphorins are another type of signaling molecule that can bind to neuropilin 1 and 2 — usually alongside another semaphorin receptor. Semaphorins are important in fetal development of the nervous system. Beyond their role in early development, semaphorins are also important in nerve function and the immune system.

Semaphorins in the immune system bind with the NRP1 and NRP2 receptors on macrophages and neutrophils. When semaphorins bind to neutrophils, they inhibit the migration of neutrophils. With macrophages, certain semaphorins promote macrophages towards a role in the resolution of inflammation, while other semaphorins promote macrophages to be pro-inflammatory.[ref]

Autoimmune diseases:

Recent research points to neuropilin 1 as a key characteristic of a type of T helper cell that is self-reactive. Most T helper cells keep the immune system in check, but self-reactive T helper cells have been identified as a key in systemic autoimmune diseases. By identifying neuropilin 1 as a key differentiator of the self-reactive T helper cells, researchers may be able to target the cells.[ref]


Neuropilin Genotype Report

Members: Log in to see your data below.
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the members only information in the Lifehacks sections.

 

NRP1 gene: encodes neuropilin 1, which is important in creating new blood vessels, vascular permeability, and immune response.

Check your genetic data for rs2228638 V7311I (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: increased risk of cyanotic congenital heart disease, TOF
  • T/T: increased risk of cyanotic congenital heart disease[ref][ref], increased relative risk of tetralogy of Fallot (TOF)[ref]

Members: Your genotype for rs2228638 is .

Check your genetic data for rs10080 (23andMe v5):

  • A/A: typical response
  • A/G: common variant in Caucasians
  • G/G: linked to altered neurological response to COVID-19[ref]

Members: Your genotype for rs10080 is .

Check your genetic data for rs2506142 (AncestryDNA):

  • G/G: 2-fold increased risk of menstrual migraines[ref]
  • A/G: increased risk for menstrual migraines
  • A/A: typical

Members: Your genotype for rs2506142 is .

NRP2 gene: encodes the neuropilin 2 receptor, which is important in the formation of lymphatic vessels and lymphatic valves. NRP2 is also found on immune system cells.

Check your genetic data for rs849563 (AncestryDNA):

  • G/G: increased relative risk of autism spectrum disorder[ref][ref], increased risk of secondary lymphedema[ref]
  • G/T: increased relative risk of autism spectrum disorder[ref]
  • T/T: typical

Members: Your genotype for rs849563 is .

Check your genetic data for rs849530 (AncestryDNA):

  • C/C: increased risk of secondary lymphedema[ref]
  • A/C: increased risk of secondary lymphedema[ref]
  • A/A: typical

Members: Your genotype for rs849530 is .


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References:

Battin, Claire, et al. “Neuropilin-1 Acts as a Receptor for Complement Split Products.” Frontiers in Immunology, vol. 10, 2019, p. 2209. PubMed, https://doi.org/10.3389/fimmu.2019.02209.

Chapoval, Svetlana P., and Achsah D. Keegan. “Perspectives and Potential Approaches for Targeting Neuropilin 1 in SARS-CoV-2 Infection.” Molecular Medicine, vol. 27, no. 1, Dec. 2021, p. 162. BioMed Central, https://doi.org/10.1186/s10020-021-00423-y.

Charfeddine, Salma, et al. “Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study.” Frontiers in Cardiovascular Medicine, vol. 8, 2021, p. 745758. PubMed, https://doi.org/10.3389/fcvm.2021.745758.

Fan, Sai-Hou, et al. “Functional Polymorphisms of the Neuropilin 1 Gene Are Associated with the Risk of Tetralogy of Fallot in a Chinese Han Population.” Gene, vol. 653, May 2018, pp. 72–79. PubMed, https://doi.org/10.1016/j.gene.2018.02.027.

Gudowska-Sawczuk, Monika, and Barbara Mroczko. “The Role of Neuropilin-1 (NRP-1) in SARS-CoV-2 Infection: Review.” Journal of Clinical Medicine, vol. 10, no. 13, June 2021, p. 2772. PubMed, https://doi.org/10.3390/jcm10132772.

Hosseinpour, Marziyeh, et al. “Neuropilin-2 Rs849563 Gene Variations and Susceptibility to Autism in Iranian Population: A Case-Control Study.” Metabolic Brain Disease, vol. 32, no. 5, Oct. 2017, pp. 1471–74. PubMed, https://doi.org/10.1007/s11011-017-0024-2.

Kyrou, Ioannis, et al. “Not Only ACE2—the Quest for Additional Host Cell Mediators of SARS-CoV-2 Infection: Neuropilin-1 (NRP1) as a Novel SARS-CoV-2 Host Cell Entry Mediator Implicated in COVID-19.” Signal Transduction and Targeted Therapy, vol. 6, no. 1, Jan. 2021, pp. 1–3. www.nature.com, https://doi.org/10.1038/s41392-020-00460-9.

Marone, Gianni, et al. “Mast Cells and Basophils in Inflammatory and Tumor Angiogenesis and Lymphangiogenesis.” European Journal of Pharmacology, vol. 778, May 2016, pp. 146–51. PubMed, https://doi.org/10.1016/j.ejphar.2015.03.088.

Patterson, Bruce K., et al. “Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection.” Frontiers in Immunology, vol. 12, 2022. Frontiers, https://www.frontiersin.org/articles/10.3389/fimmu.2021.746021.

Raveney, Ben JE, et al. “Neuropilin‐1 ( NRP1 ) Expression Distinguishes Self‐reactive Helper T Cells in Systemic Autoimmune Disease.” EMBO Molecular Medicine, Sept. 2022. DOI.org (Crossref), https://doi.org/10.15252/emmm.202215864.

Roy, Sohini, et al. “Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy.” Frontiers in Immunology, vol. 8, 2017. Frontiers, https://www.frontiersin.org/articles/10.3389/fimmu.2017.01228.

Stuart, Lynda M. “In Gratitude for MRNA Vaccines.” New England Journal of Medicine, edited by Elizabeth G. Phimister, vol. 385, no. 15, Oct. 2021, pp. 1436–38. DOI.org (Crossref), https://doi.org/10.1056/NEJMcibr2111445.

Sulpice, Eric, et al. “Neuropilin-1 and Neuropilin-2 Act as Coreceptors, Potentiating Proangiogenic Activity.” Blood, vol. 111, no. 4, Feb. 2008, pp. 2036–45. PubMed, https://doi.org/10.1182/blood-2007-04-084269.

Vilella, F., et al. “Single-Cell RNA Sequencing of SARS-CoV-2 Cell Entry Factors in the Preconceptional Human Endometrium.” Human Reproduction (Oxford, England), vol. 36, no. 10, Sept. 2021, pp. 2709–19. PubMed, https://doi.org/10.1093/humrep/deab183.

Wu, Suping, et al. “Association of the Neuropilin-2 (NRP2) Gene Polymorphisms with Autism in Chinese Han Population.” American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, vol. 144B, no. 4, June 2007, pp. 492–95. PubMed, https://doi.org/10.1002/ajmg.b.30495.

Xu, Jing, et al. “Genetic Variants at 10p11 Confer Risk of Tetralogy of Fallot in Chinese of Nanjing.” PloS One, vol. 9, no. 3, 2014, p. e89636. PubMed, https://doi.org/10.1371/journal.pone.0089636.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.