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, migraines, 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
• Plays a role in the gut barrier (prevents leaky gut)[ref]

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.

For example:

• 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, and 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:

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 cellular junctions are in the endothelium, allowing plasma and other things to flow in and 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]

Gut barrier function (preventing leaky gut):

In addition to the well-known role in regulating blood vessels, neuropilin has recently been discovered to have an important role in how the gut barrier functions.

The epithelial cells lining the intestines play a vital role in keeping the bacteria and viruses solidly in the gut microbiome and preventing them from moving into the bloodstream. There are several different proteins (claudins, zonulin) that keep the junctions between intestinal epithelial cells tight. Neuropilin receptors on the gut epithelial cells act as a feedback loop in regulating the gut barrier function through the interaction of gut microbes with TLR2. Essentially, more NLRP means tight junctions.[ref]

Lymphedema:

Rare mutations in the NRP1 and NRP2 genes are linked to significantly 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 subtypes of VEGF are also important in the development of the lymphatic system. Neuropilin interacts with VEGF in the promotion of the growth of vessels (blood and lymph).

More specifically, 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]

Viral entry for other viruses:

In addition to SARS-CoV-2, the neuropilins are also involved in the way that other viruses can get into cells.  For example, NRP1 is a receptor for Epstein-Barr virus (EBV), Human T-cell Lymphotropic virus type 1, and enterovirus 71. NRP2 is a receptor for cytomegalovirus.[ref]

The important connection here – neuropilins are also found in the intestinal barrier epithelial cells and could be an entry point for viruses in the intestines.

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]

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]

Lifehacks:

The Lifehacks section is normally where I would list a bunch of supplements and OTC medications that impact the gene of interest… But, for neuropilin 1 and 2, blocking the receptor will affect how blood vessels are formed. While this may be positive in specific tissues in cancer patients, in general, blocking the neuropilins could negatively impact wound healing, ovulation, menstruation, blood pressure, and possibly immune function.[ref]

Instead, I will speculate here on how NRP1 could be important in long covid and/or spike protein vaccine-related issues.

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