Table I.
Protease | Common Aliases | Gene Symbol | Membrane Anchor | In Vivo Vascular and Extravascular Functions | Ref. |
---|---|---|---|---|---|
Serine Proteases | |||||
Membrane-anchored Serine Proteases | |||||
Prostasin | PRSS8, CAP1 | PRSS8 | GPI | Epidermal deficiency causes defective barrier function in mice. Tissue specific deletion in mice shows reduced fluid clearance in lung and colonic epithelium due to defects in ENaC activation. Liver specific knock-out mice develop insulin resistance associated with associated with reduced hepatic TLR-4 shedding. Implicated in blood pressure regulation in humans. | [2–8] |
Matriptase | MT-SP1, CAP3, ST14, PRSS14, epithin | ST14 | Type II | Null and hypomorphic mice show defective global epithelial barrier function due to increased paracellular permeability. Activates the c-Met ligand pro-HGF/SF when over expressed in keratinocytes in mice. | [9–11] |
Matriptase-2 | TMPRSS6 | TMPRSS6 | Type II | Essential for iron homeostasis by cleavage of hemajuvelin, prevents iron-refractory iron deficiency anemia in humans. Over-expression in human vascular endothelial cells inhibits tumor induced angiogenesis in a murine xenograft model. | [12,13] |
Corin | LRP4, ATC2, TMPRSS10 | CORIN | Type II | Important regulator of blood pressure and volume via the activation of natriuretic peptides in cardiomyocytes. Promotes uterine spiral artery remodeling during pregnancy. | [14–16] |
Proprotein convertases | |||||
Furin | Paired basic amino acid cleaving enzyme, FUR, PACE, SPC1, PCSK3 | FURIN | Type I | Null mice are embryonic lethal due to a failure of ventral closure and large blood vessel development. Endothelial cell specific knockout mice die due to cardiovascular dysfunction. | [17,18] |
Prolyl oligopeptidases (POP) | |||||
DPPIV | Dipeptidyl peptidase 4, CD26 | DPP4 | Type II | Regulates vascular endothelial cell function. Inactivates stromal cell-derived factor-1 (SDF-1), a key regulator of vascular stem cell homing. Inhibition lowers blood pressure, decreases cardiovascular disease and improves outcomes after myocardial infarction in mice. | [19–22] |
Metalloproteases | |||||
Membrane-type | |||||
MT1-MMP | MMP14, MT-MMP1 | MMP14 | Type I | Null mice show reduced vascular invasion of cartilage and defective corneal angiogenesis in response to basic fibroblast growth factor. | [23–25] |
MT4-MMP | MMP17, MT-MMP4 | MMP17 | GPI | Deficiency predisposes mice to aortic aneurysm due to dysfunctional vascular smooth muscle cells. Loss of expression in patients with hereditary thoracic aortic aneurysms increases susceptibility to aneurysm rupture. | [26**] |
ADAM Proteases | |||||
ADAM8 | CD156, cell surface antigen MS2, human leukocyte differentiation antigen | ADAM8 | Type I | Null mice show increased branching and vessel density in pathological retinal neovascularization assays. | [27–29] |
ADAM9 | meltrin gamma, cellular disintegrin- related protein | ADAM9 | Type I | Murine deficiency inhibits pathological retinal neovascularization in oxygen-induced retinopathy and laser-induced choroidal models. | [27,30] |
ADAM10 | CD156c, kuzbanian protein homolog, mammalian disintegrin- metalloprotease | ADAM10 | Type I | Murine deficiency is embryonic lethal due to defective blood vessel development. Endothelial cell specific deficiency, or inhibition of ADAM10, causes increased pathological retinal neovascularization following oxygen-induced retinopathy. | [27,31, 32*] |
ADAM12 | Meltrin alpha, metalloprotease- disintegrin 12 transmembrane | ADAM12 | Type I | Knockdown of ADAM12 in mice inhibits recovery from experimental peripheral artery disease. Inhibition of ADAM12 in mice reduces hypoxia-induced impairment of neural vascular barrier function. | [2,27,33,34**] |
ADAM15 | Metargidin, a disintegrin and metalloproteinase domain 15 | ADAM15 | Type I | Null mice or mice carrying an active site mutation, show decreased pathological retinal neovascularization following oxygen-induced retinopathy. Null mice show a reduction in the development of atherosclerotic lesions caused by apolipoprotein E-deficiency. Mediates endothelial hyperpermeability during acute lung injury induced by lipopolysaccharide in mice. | [27,35– 37] |
ADAM17 | TNF-alpha converting enzyme (TACE), ADAM metallopeptidase domain 18 | ADAM17 | Type 1 | Murine deficiency or mice lacking the ADAM17 Zn binding site have defective blood vessel formation causing death. Endothelial cell specific deficiency or ADAM17 inhibition causes reduced pathological retinal neovascularization. Inhibition in mice reduces hypoxia-induced impairment of neural vascular barrier function. | [2,27,32,34,38] |
ADAM33 | disintegrin and reprolysin metalloproteinase family protein | ADAM33 | Type I | Susceptibility gene for asthma and chronic obstructive pulmonary disorder. Soluble form is found in asthmatic bronchiolar lavage fluid and promotes human endothelial cell differentiation and tube formation in vitro, and neovascularization in the chorioallantoic membrane assay. Also implicated in the pathogenesis of atherosclerosis. | [27,39– 41] |
Angiotensin- converting enzymes | |||||
ACE | angiotensin- converting enzyme, ACE1, CD143, carboxycathepsin, dipeptidyl carboxypeptidase 1 | ACE | Type I | Catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor causing increased blood pressure. ACE inhibitors are the primary treatment for hypertension. Over-expression is correlated with cardiovascular diseases. | [42,43] |
ACE2 | angiotensin- converting enzyme 2, ACEH, ACE- related carboxypeptidase | ACE2 | Type I | Acts as a counter-regulatory mechanism to ACE1 by cleaving angiotensin II to angiotensin products with vasodilator and vasoprotective properties. | [44,45] |
Abbreviations: ADAM, a disintegrin and metalloproteinase; ENaC, epithelial sodium channel; MMP, matrix metalloproteinases; MT-MMP, membrane tethered-matrix metalloprotease; pro-HGF/SF, pro-hepatocyte growth factor/scatter factor; PRSS, protease serine S1; PSCK, proprotein convertase subtilisin/kexin type; TLR, toll-like receptor; TMPRSS, transmembrane protease serine S1.