The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis

Abstract

Objective. Postnatal angiogenesis relies on a proper response of endothelial cells to angiogenic stimuli. In systemic sclerosis (SSc), endothelial cells are unresponsive to angiogenic factors. Since circumstantial and experimental evidence points to tissue kallikreins as powerful effectors of the angiogenic response, we undertook this study to investigate the kallikrein pattern of normal and SSc endothelial cells in order to identify differences that can account for defective angiogenesis.Methods. Expression of 14 tissue kallikreins was studied by a microarray approach, by reverse transcription-polymerase chain reaction, and by Western blotting in endothelial cells isolated from the skin of clinically healthy subjects and SSc patients. Cell proliferation was quantified by direct cell counting. Invasion and capillary morphogenesis were evaluated in a Boyden chamber and in culture flasks layered with Matrigel. Cyclic nucleotide production was measured by enzyme immunoassay. MAP kinase and ERK activation were measured by Western blotting.Results. Endothelial cells from SSc patients showed poor expression of kallikreins 9, 11, and 12 compared with endothelial cells from normal subjects. Antibodies against the relevant kallikreins on normal endothelial cells revealed that while kallikreins 9, 11, and 12 induced cell growth, only kallikrein 12 regulated invasion and capillary morphogenesis. Buffering of kallikrein 12 with antibodies resulted in the acquisition of an SSc-like pattern by normal cells in in vitro angiogenesis. Reduction of cAMP and cGMP production and of ERK phosphorylation upon administration of antikallikrein antibodies revealed that the activity of kallikreins 9, 11, and 12 was mediated by kinins.Conclusion. Reduction of tissue kallikreins 9, 11, and 12 may be relevant to reduced angiogenesis in SSc patients.

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

“…Blockage of KLK12 activity with specific anti-KLK12 antibodies was reported to reduce proliferation, migration, and formation of branching cords of microvascular endothelial cell in vitro. Furthermore, its expression is down-regulated in endothelial cells from patients with systemic sclerosis displaying defective angiogenesis compared with endothelial cells from normal subjects (9). Because KLK12 seems to play a critical role in controlling normal angiogenesis, we sought to investigate the relations between KLK12, CCNs, and factors regulating angiogenesis.…”

“…So far, 15 members of the family (KLK1-15) have been identified and found expressed in a large number of tissues and cell populations (1). KLKs play important roles in different pathophysiologic processes (2) such as skin desquamation (3), innate immunity (4), semen liquefaction (5), dental enamel formation (6), neuro-degeneration (7), cervicovaginal physiology (8), and angiogenesis (9). Furthermore, dysregulated kallikreinrelated peptidase gene and protein expression has been implicated in cancer (10).…”

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

“…At present, kinin is the only recognized terminal inducer of sperm motility (63). Active kinins are released from seminal kininogens through limited proteolysis by a number of kininogenases, including KLK1 (64,65). Sperm motility is believed to be mediated through the B2R (B2 subtype of bradykinin) receptor and subsequent release of intracellular Ca 2ϩ in testicular peritubular cells (62,66).…”

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…Prostate cancer KLK1 Promotion of cell invasiveness; angiogenesis Emanueli et al, 2001;Giusti et al, 2005;Gao et al, 2010 KLK2 Tumor growth promotion; ECM degradation Deperthes et al, 1996;Takayama et al, 1997;Mikolajczyk et al, 1999;Rehault et al, 2001;Mize et al, 2008 PSA/KLK3 Tumor growth promotion; EMT-like changes; ECM degradation; angiogenesis; metastasis Webber et al, 1995;Cramer et al, 1996;Fortier et al, 1999;Sun et al, 2001;Yonou et al, 2001;Koistinen et al, 2002;Ishii et al, 2004;Pezzato et al, 2004;Romanov et al, 2004;Dallas et al, 2005;Veveris-Lowe et al, 2005;Goya et al, 2006;Nadiminty et al, 2006 KLK4 Tumor growth promotion; EMT-like changes; ECM degradation; metastasis Takayama et al, 2001;Matsumura et al, 2005;Veveris-Lowe et al, 2005;Beaufort et al, 2006;Gao et al, 2007;Klokk et al, 2007;Mize et al, 2008;Ramsay et al, 2008a;Wang et al, 2010 KLK7 EMT-like changes; promotion of cell invasiveness Mo et al, 2010 KLK14 Tumor growth promotion; ECM degradation Borgono et al, 2007b Breast cancer KLK1 Promotion of cell invasiveness; angiogenesis Emanueli et al, 2001;Wolf et al, 2001;Giusti et al, 2005 PSA/KLK3 Tumor suppressor Lai et al, 1996 KLK6 Tumor suppressor; inhibition of cells invasiveness; antiangiogenes...…”

“…The observation that KLK12 blockage was accompanied by a signifi cant reduction in cAMP and cGMP concentration and in ERK phosphorylation indicates that the angiogenic role of KLK12 relies upon the stimulation of kinin-dependent signaling. KLK1-mediated activation of kinin-downstream cascades has been revealed in prostate cancer angiogenesis (Giusti et al , 2005 ). A more recent study proposed an alternative molecular pathway for the explanation of KLK12-stimulated angiogenesis.…”