Table 3 Lymphangiogenesis in other diseases

Chronic obstructive pulmonary disease

1. Lymphangiogenesis is beneficial in reducing lymphedema and airflow obstruction.

2. Lymphangiogenesis increases immune cell trafficking in patients with advanced chronic obstructive pulmonary disease.

1. Inflammatory cells and epithelial cells promote lymphangiogenesis through the regulation of VEGFC and VEGFD.

2. The expression of CCL21 and chemokine scavenger receptor D6 in LECs of perialveolar lymphatic vessels is increased, which promotes the delivery of immune cells.

^464,465

Asthma

Impaired lymphangiogenesis disrupts antigen clearance from the lungs and airways.

IL-13 and IL-4 secreted by Th2 cells are identified as potent inhibitors of lymphangiogenesis via JAK/STAT pathways, resulting in the downregulation of PROX1 expression.

⁴⁶⁶

Tuberculosis

1. Lymphangiogenesis induced by Mycobacterium tuberculosis granulomas promotes a systemic T cell response against Mycobacterium tuberculosis antigens.

2. LEC in lymph node provides with the natural niche for Mycobacterium tuberculosis replication.

1. Mycobacterium tuberculosis granulomas promote lymphangiogenesis through the VEGFC/VEGFR3 pathway.

2. Replication of Mycobacterium tuberculosis in the cytoplasmic and phagosome of LECs is dependent on the presence of RD1(encoding ESX-1).

^467,468

Idiopathic pulmonary fibrosis

1. Perialveolar lymphangiogenesis is positively correlated with the degree of pulmonary fibrosis.

2. Abnormal mural cell coverage of pulmonary lymphatic vessels and impaired lymphatic drainage lead to pulmonary fibrosis.

1. Increased hyaluronic acid and macrophage transdifferentiation promote alveolar lymphangiogenesis.

2. The recruitment of mural cells is facilitated by LECs through the PDGFβ/PDGFRβ pathway, resulting in compromised lymphatic drainage and promoting fibroblast aggregation, ultimately leading to the development of pulmonary fibrosis.

^469,470

Heart failure

Endogenous cardiac lymphangiogenesis limits cardiac inflammation and perivascular fibrosis, delaying heart faliure development.

Activation of the VEGFC/VEGFR3 signaling prevents the progression to heart failure.

^471,472

Atherosclerosis

1.Lymphangiogenesis dampens the local inflammatory response at an early stage of plaque development.

2.Disrupted arterial lymphangiogenesis impairs cholesterol efflux from atherosclerotic arteries.

1.Plaque-associated lymphangiogenesis is partly drove by CXCL12/CXCR4 axis.

2.Increased level of RSPO2 binding to LGR4 in atherosclerotic arteries inhibits lymphangiogenesis through impairment of VEGFC-induced AKT/eNOS/NO signaling.

^117,473

Myocardial infarction

1.Lymphagiogenesis contributes to the fibrosis maturation and scar formation by eliminating excess protein and fluid in granulation and scar phase.

2.Lymphangiogenesis improves cardiac function and suppresses cardiac edema.

3.Lymphoangiocrine signal produced by LECs is cardioprotective, which contributes to reduced cardiomyocytes death and a smaller scarred myocardial area.4.Lymphangiogenesis prompts LEC penetration into the infarcted myocardium, and activated LECs function as intramyocardial immune hubs promote the formation of immunosuppressive microenvironment, facilitating post-myocardial infarction repair.

1.VEGFC expressed by cardiomyocytes induces lymphagiogenesis in/around the infarcted lesion.

2.Epicardial-secreted factor Adrenomedullin drives reparative cardiac lymphangiogenesis and function via CX43.

3.LECs-secreted Reelin regulates cardiomyocytes proliferation and survival through the Integrinβ1 signaling pathway.

4.TBX1 in LECs drives a bi-functional LEC transcriptional program that not only promotes lymphangiogenesis but also enhances the immunosuppressive function which mediated by the expression of CCL21 and ICAM1.

^{285,474,475,476}

Non-alcoholic fatty liver disease

1.Disrupt lymphangiogenesis impedes lymphatic vessel stability and liver homeostasis by regulating fibrosis development and immune cell infiltration.

2. Decreased lymphatic permeability disrupts protein homeostasis and increases inflammation, which is based on impeded LEC metabolism and reorganized cell-cell junctions.

1.OxLDL stimulates the expression of IL-13, thereby inhibiting lymphangiogenesis and affecting lymphatic vessel stability.

2.OxLDL downregulates PROX1, LYVE1, PDPN, and VEGFR3 expression in LECs, which impacts lymphangiogenesis and lymphatic permeability.

^477,478

Cirrhotic liver

Hepatic lymphangiogenesis promoted by sympathetic nerves prevents liver from portal tract fibrosis.

VEGFC expressed by Schwann cells of sympathetic nerves promotes hepatic lymphangiogenesis.

⁴⁷⁹

Endometriosis

Lymphangiogenesis promotes the infiltration of immune cells, aggravating local chronic inflammation and endometriosis development.

1.IL-1β and TNF-α modulate the overexpression of VEGFC via suppressing COUP-TFII in endometriotic stromal cells, which promotes lymphangiogenesis.

2.Upregulated BST2 regulates the transcription of VEGFC via the activation of NF-κB signaling pathway in endometriotic stromal cells, which promotes lymphangiogenesis.

^480,481

Arthritis

1.Lymphangiogenesis compensatorily improves joint inflammation during chronic arthritis.

2.Induced lymphangiogenesis improves synovial lymphatic drainage and alleviates arthritis damage in age-related osteoarthritis.

1.Circulating CD11b⁺ myeloid cells infiltrate in joint inflammation, which produce VEGFC to stimulate lymphangiogenesis.

2.Activation of VEGFC/VEGFR3 signaling pathway stimulates synovial lymphangiogenesis.

^482,483