Researchers have investigated LL-37 in vascular biology using endothelial cell models and experimental models of angiogenesis. Researchers have examined its effects on endothelial behavior and vascularization. The research includes endothelial migration, proliferation, vessel formation, angiogenic signaling and vascular responses in experimental models. Separate research has examined LL-37-induced responses in lymphatic endothelial cells. These studies provide experimental evidence from endothelial cell assays, ex vivo vascular models, tissue vascularization models, and lymphatic endothelial systems.
LL-37 and Endothelial Cell Responses
Endothelial Cell Migration
The 2025 study examined LL-37 associated migration in human umbilical vein endothelial cells (HUVECs) using scratch and Transwell migration assays.
The scratch assay showed a significantly greater average migration distance in LL37 treated HUVECs at 24 and 48 hours than in the control group. The Transwell migration assay also showed significantly more membrane-penetrating cells after LL37 treatment.
Endothelial Cell Proliferation
The 2003 study examined proliferation in cultivated HUVECs. LL-37 produced a dose dependent increase in endothelial cell proliferation during the reported 72 hour experiment.
The 2025 study measured HUVEC proliferation using CCK-8 and plate-cloning assays. LL-37 treatment increased the proliferation measurements reported in both assays compared with the control group.
Vessel-Like Structure Formation
The 2003 study examined LL-37 in a Matrigel assay using cultivated endothelial cells. LL-37 produced visible rings and cords of endothelial cells in the assay. The study also used a hamster aortic-ring sprouting assay and reported increased endothelial sprouting after LL-37 exposure.
The 2025 study used an angiogenesis assay with HUVECs and reported increased tube formation after LL-37 exposure. The reported measurements included branch numbers and cumulative tube length.
Signaling Mechanisms Studied in LL-37 Angiogenesis
FPR2/ALX Signaling
The 2003 study investigated formyl peptide receptor-like 1 (FPRL1) in endothelial cells. FPRL1 transcripts and protein were detected in HUVECs. FPRL1 protein was also detected in endothelial cells in human lung tissue.
The researchers used the FPRL1 agonist WKYMVm to examine receptor activity. WKYMVm increased endothelial proliferation. An antiserum against FPRL1 blocked the proliferative effect produced by LL-37. Pertussis toxin also abolished the effects of LL-37 on endothelial cells, including proliferation. The study identified FPRL1 as a mediator of the LL-37-induced angiogenic response.
FPRL1 is also referred to as FPR2/ALX in receptor nomenclature.
cPLA2–COX-1–PGE2–EP3 Signaling
The 2013 study examined LL-37-induced PGE2 synthesis in endothelial cells. LL-37 increased PGE2 production in a dose-dependent manner, with maximum induction reported after four hours. Pharmacological inhibition and gene-silencing experiments showed that PGE2 biosynthesis depended on COX-1 rather than COX-2.
LL-37 also acted as a calcium agonist and induced phosphorylation and activation of cytosolic phospholipase A2 (cPLA2). The study identified a cPLA2 to COX-1 to PGE2 pathway followed by signaling through the PGE2 receptor EP3.
In Matrigel experiments, LL-37-induced cord formation was abolished by COX-1 small interfering RNA, while COX-2 small interfering RNA did not produce the same effect. Addition of exogenous PGE2 rescued the angiogenic phenotype after COX-1 suppression.
LL-37 and Vascularization in Experimental Models
Chorioallantoic Membrane Neovascularization
The 2003 study used the chorioallantoic membrane (CAM) assay to examine neovascularization. LL-37 treatment increased vascular growth in the CAM model. The researchers reported increased numbers of erythrocyte-filled vessels in LL-37-treated samples.
Hind-Limb Vascularization
The 2003 study used a rabbit hind-limb ischemia model to examine collateral growth, capillary density and blood-flow velocity. LL-37 treatment increased collateral vessel growth and capillary density. Blood-flow velocity was also higher in the LL-37-treated group.
In the 2025 mouse model of lower-limb ischemia. Laser Doppler flowmetry measured lower-limb perfusion. LL-37 treatment significantly improved perfusion in the ischemic limb. Immunofluorescence analysis showed higher CD31 and CD34 expression in the LL-37 group.
LL-37 and Lymphatic Endothelial Responses
A 2020 study examined LL-37 in human dermal lymphatic microvascular endothelial cells (HDLECs). LL-37 treatment increased HDLEC migration and tube like formation. The study also reported increased expression of a lymphangiogenic factor in LL-37-treated cells.
LL-37 increased ERK and Akt phosphorylation in HDLECs. Pretreatment with ERK or Akt inhibitors reduced the LL-37-induced migration and tube-like formation responses.
The study also examined FPRL1 with an FPRL1 antagonist. Antagonist pretreatment reduced LL-37-induced ERK and Akt phosphorylation and attenuated the migration and tube-like formation responses. The authors reported that LL-37-induced lymphangiogenesis involved FPRL1 and ERK/Akt signaling.
Limitations of Current LL-37 Angiogenesis Research
The studies use different endothelial cell models and experimental systems. The 2003 study examined cultivated endothelial cells, aortic-ring sprouting, CAM neovascularization, and rabbit hind-limb vascularization. The 2025 study used HUVEC assays and a mouse lower-limb ischemia model. The 2020 study examined lymphatic endothelial cells.
The experimental assays and molecular endpoints also differ between studies. The reported systems include cell migration, proliferation, tube formation, vascular sprouting, vessel counting, capillary density, blood-flow measurements, endothelial markers and signaling measurements. These differences limit direct comparison between individual experimental models.
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References
- Koczulla R, von Degenfeld G, Kupatt C, Krötz F, Zahler S, Gloe T, Issbrücker K, Unterberger P, Zaiou M, Lebherz C, Karl A, Raake P, Pfosser A, Boekstegers P, Welsch U, Hiemstra PS, Vogelmeier C, Gallo RL, Clauss M, Bals R. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003 Jun;111(11):1665-72. d PubMed ↗
- Salvado MD, Di Gennaro A, Lindbom L, Agerberth B, Haeggström JZ. Cathelicidin LL-37 induces angiogenesis via PGE2-EP3 signaling in endothelial cells, in vivo inhibition by aspirin. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1965-72. PubMed ↗
- Yanagisawa T, Ishii M, Takahashi M, Fujishima K, Nishimura M. Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways. Mol Biol Rep. 2020 Sep;47(9):6841-6854. PubMed ↗
- Yang Y, Wu G, Wang Y, Mao Q, Zhang D, Wu J. LL37 promotes angiogenesis: a potential therapeutic strategy for lower limb ischemic diseases. Front Pharmacol. 2025 Apr 23;16:1587351. PubMed ↗