Tissue Kallikrein is essential for invasive capacity of circulating proangiogenic cells

Gaia Spinetti, Orazio Fortunato, Daniela Cordella, Paola Portararo, Nicolle Kränkel, Rajesh Katare, Graciela B. Sala-Newby, Christine Richer, Marie Pascale Vincent, Francois Alhenc-Gelas, Giancarlo Tonolo, Sara Cherchi, Costanza Emanueli, Paolo Madeddu

Research output: Contribution to journalArticle

Abstract

Rationale: Homing of proangiogenic cells (PACs) is guided by chemoattractants and requires proteases to disrupt the extracellular matrix. The possibility that PAC recruitment involves an interaction between proteases and chemotactic factor receptors remains largely unexplored. Objective: To determine the role of human tissue kallikrein (hK1) in PAC invasion and its dependency on kinin receptor signaling. Methods and Results: Human mononuclear cells (MNCs) and culture-selected PACs express and release mature hK1 protein. HK1 gene (KLK1) silencing reduced PACs migratory, invasive, and proangiogenic activities. KLK1-knockout mouse bone marrow-derived MNCs showed similar impairments and were unable to support reparative angiogenesis in a mouse model of peripheral ischemia. Conversely, adenovirus-mediated KLK1 (Ad.KLK1) gene transfer enhanced PAC-associated functions, whereas the catalytically inactive variant R53H-KLK1 was ineffective. HK1-induced effects are mediated by a kinin B2 receptor (B2R)-dependent mechanism involving inducible nitric oxide synthase and metalloproteinase-2 (MMP2). Lower hK1 protein levels were observed in PACs from type 2 diabetic (T2D) patients, whereas KLK1 mRNA levels were similar to those of healthy subjects, suggesting a post-transcriptional defect. Furthermore, B2R is normally expressed on T2D-PACs but remains uncoupled from downstream signaling. Importantly, whereas Ad.KLK1 alone could not restore T2D-PAC invasion capacity, combined KLK1 and B2R expression rescued the diabetic phenotype. Conclusions: This study reveals new interactive components of the PACs invasive machinery, acting via protease- and kinin receptor-dependent mechanisms.

Original languageEnglish
Pages (from-to)284-293
Number of pages10
JournalCirculation Research
Volume108
Issue number3
DOIs
Publication statusPublished - Feb 4 2011

Keywords

  • angiogenesis
  • cell invasion
  • circulating proangiogenic cells
  • kallikrein- kinin system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Spinetti, G., Fortunato, O., Cordella, D., Portararo, P., Kränkel, N., Katare, R., Sala-Newby, G. B., Richer, C., Vincent, M. P., Alhenc-Gelas, F., Tonolo, G., Cherchi, S., Emanueli, C., & Madeddu, P. (2011). Tissue Kallikrein is essential for invasive capacity of circulating proangiogenic cells. Circulation Research, 108(3), 284-293. https://doi.org/10.1161/CIRCRESAHA.110.236786