The molecular mechanism by which L-Arginine promotes wound healing

As a semi-essential amino acid in the human body, L-arginine plays a crucial regulatory role in the wound healing process. Its function is not achieved through a single pathway but rather through the synergistic activation of a "cascade reaction" for wound repair via multi-dimensional molecular mechanisms, covering core links such as cell proliferation, angiogenesis, inflammation regulation, and tissue remodeling. The specific molecular mechanisms can be elaborated from the following four aspects:

I. Activating Multiple Repair Pathways Through Nitric Oxide (NO) Production

L-arginine is the sole substrate for nitric oxide synthase (NOS). In macrophages, endothelial cells, and fibroblasts at the wound site, NOS can convert L-arginine into NO—and as a vital signaling molecule, NO serves as the core "molecular switch" driving wound healing.

On one hand, NO activates guanylate cyclase in vascular endothelial cells, increasing the level of cyclic guanosine monophosphate (cGMP). This in turn relaxes vascular smooth muscle, dilates local microvessels, and enhances vascular permeability, delivering more oxygen, nutrients (e.g., glucose, amino acids), and immune cells to the wound area while alleviating the hypoxic microenvironment at the wound site. Hypoxia is a key barrier to delayed healing, and the improved blood flow mediated by NO directly provides an "energy and raw material foundation" for subsequent cell proliferation.

On the other hand, NO can regulate the expression of cell cycle-related proteins (e.g., cyclin D1, p21) to promote the proliferation and migration of fibroblasts and keratinocytes:

Fibroblasts are the core cells responsible for collagen synthesis, and enhanced proliferation capacity accelerates granulation tissue formation.

The migration of keratinocytes drives wound epithelialization, shortening the duration of wound exposure.

Additionally, NO inhibits excessive platelet aggregation to prevent local thrombus formation (which would impede blood flow) and suppresses the overactivation of neutrophils to reduce oxidative stress damage, thereby balancing the local microenvironment at the wound site.

II. Regulating Inflammatory Response: Precise Switching from "Pro-Inflammatory" to "Anti-Inflammatory"

A moderate inflammatory response is required in the early stage of wound healing to clear necrotic tissue and pathogens, but excessive or persistent inflammation disrupts the repair process. L-arginine enables "dynamic balance" of the inflammatory response through molecular regulation.

In the inflammatory initiation phase, L-arginine enhances the phagocytic capacity of macrophages by producing NO: NO activates the activity of lysosomal enzymes in macrophages to promote pathogen degradation, while also inducing macrophages to secrete pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). These factors recruit more immune cells to the wound site, initiating the first step of "wound cleansing."

As healing progresses, L-arginine regulates inflammatory resolution through a switch in metabolic pathways: its metabolite ornithine can be further converted into polyamines (e.g., putrescine, spermidine), which inhibit the activation of nuclear factor-κB (NF-κB)—the core transcription factor for pro-inflammatory factor expression. Inhibiting NF-κB activity reduces the release of pro-inflammatory factors. Meanwhile, L-arginine promotes the transformation of macrophages into the "anti-inflammatory phenotype" (M2 type). Anti-inflammatory factors secreted by M2 macrophages, such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), inhibit the excessive infiltration of neutrophils, creating a "non-inflammatory environment" for fibroblast proliferation and angiogenesis.

III. Promoting Angiogenesis: Building a "Nutrient Transport Network" for Wound Repair

Wound healing relies on newly formed blood vessels to supply energy to local tissues. L-arginine drives the angiogenesis process by directly regulating vascular endothelial cell function and the expression of related cytokines.

In terms of direct effects:

L-arginine is an essential amino acid for endothelial cell proliferation, and its metabolite NO also inhibits endothelial cell apoptosis: NO activates the expression of the anti-apoptotic protein Bcl-2 while inhibiting the activity of the pro-apoptotic protein Bax, reducing endothelial cell death caused by hypoxia and inflammation, and maintaining the "cellular foundation" for angiogenesis.

NO promotes endothelial cell migration and lumen formation: In in vitro experiments, supplementation with L-arginine significantly increases the migration distance of endothelial cells and induces endothelial cells to connect with each other to form tubular structures, providing support for the "morphological construction" of new blood vessels.

In terms of indirect regulation:

L-arginine promotes the expression and activity of vascular endothelial growth factor (VEGF)—the core cytokine for angiogenesis. It upregulates the transcription and translation of VEGF by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, while also enhancing the phosphorylation level of the VEGF receptor (VEGFR2) to amplify VEGF-mediated angiogenesis signals. Additionally, L-arginine promotes fibroblasts to secrete platelet-derived growth factor (PDGF), which recruits vascular smooth muscle cells to surround newly formed blood vessels, enhancing vascular stability and preventing the rupture of new blood vessels due to structural fragility.

IV. Participating in Tissue Remodeling: Strengthening the "Structural Support" for Wound Healing

Tissue remodeling is the final stage of wound healing, with the core being the synthesis, cross-linking, and orderly arrangement of collagen. L-arginine improves the quality of wound repair by regulating fibroblast function and collagen metabolism.

In terms of collagen synthesis:

The metabolite of L-arginine—ornithine—is a precursor of proline, which is a key component of collagen peptide chains (accounting for approximately 23% of the total amino acids in collagen). Supplementation with L-arginine increases intracellular ornithine reserves, thereby promoting proline synthesis and providing "raw material guarantee" for the assembly of collagen peptide chains. Meanwhile, L-arginine activates the mitogen-activated protein kinase (MAPK) signaling pathway in fibroblasts via NO, upregulating the gene expression of type I and type III collagen (e.g., COL1A1, COL3A1) and significantly increasing collagen synthesis. This avoids poor wound healing (e.g., weak scars, easy rupture) caused by insufficient collagen synthesis.

In terms of collagen cross-linking and arrangement:

L-arginine promotes the activity of lysyl oxidase (LOX)—a key enzyme for collagen cross-linking. LOX catalyzes the formation of covalent bonds between lysine residues in collagen molecules, enhancing the strength of collagen fibers. Additionally, L-arginine regulates the differentiation direction of fibroblasts, promoting their transformation into myofibroblasts: Myofibroblasts can pull the edge tissues of the wound closer through contraction, while also secreting collagenase to regulate the degradation and remodeling of collagen. This avoids scar hyperplasia caused by excessive collagen deposition, achieving "functional repair" of wound tissue.

Through four major molecular mechanisms—NO-mediated signaling pathways, inflammatory response regulation, angiogenesis promotion, and tissue remodeling support—L-arginine synergistically drives wound healing from four dimensions: "initiating repair, maintaining the environment, building the network, and strengthening the structure." Its role runs through the entire process of wound healing, providing a clear molecular theoretical basis for the clinical use of L-arginine to improve hard-to-heal wounds (e.g., diabetic foot ulcers, burn wounds).