Table I.

Membrane-anchored proteases associated with endothelial and vascular biology and their functions.

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.