Skip to main content
SpringerLink
Log in

Kruppel-Like Factor 2 and Matrix Metalloproteinases in the Context of Vasculature

  • Chapter
  • First Online:
Matrix Pathobiology and Angiogenesis

Part of the book series: Biology of Extracellular Matrix ((BEM,volume 12))

  • 255 Accesses

Abstract

Matrix metalloproteinases (MMPs) and Kruppel-like Factor 2 (KLF2) are proteins present in endothelial cells that play opposing roles in these cells in response to angiogenic and inflammatory stimuli. MMPs are endoproteases that play a large part in the degradation of various components of the extracellular matrix (ECM) and tissue remodeling. They are essential mediators of inflammation, angiogenesis, and vascular remodeling. KLF2 is a transcription factor in endothelial cells that helps maintain homeostasis and signals the endothelial cell to enter a state of quiescence. It is induced by unidirectional flow and is anti-inflammatory, anti-thrombotic, and anti-angiogenic, and promotes vasodilation. The goal of this chapter is to provide insight into this complex system by focusing on one cell type, one transcription factor, and one protease family. Herein, we review the functions of these proteins, especially in endothelial cells, and their roles in various processes, including angiogenesis, atherosclerosis, and clotting.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agren MS, Auf dem Keller U (2020) Matrix metalloproteinases: how much can they do? Int J Mol Sci 21(8)

    Google Scholar 

  • Alcantara MB, Dass CR (2013) Regulation of MT1-MMP and MMP-2 by the serpin PEDF: a promising new target for metastatic cancer. Cell Physiol Biochem 31(4–5):487–494

    Article  CAS  Google Scholar 

  • Alexander JS, Elrod JW (2002) Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. J Anat 200(6):561–574

    Article  CAS  Google Scholar 

  • Arpino V, Brock M, Gill SE (2015) The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 44-46:247–254

    Article  CAS  Google Scholar 

  • Atkins GB, Jain MK (2007) Role of Kruppel-like transcription factors in endothelial biology. Circ Res 100(12):1686–1695

    Article  CAS  Google Scholar 

  • Bedoui Y et al (2019) Methotrexate an old drug with new tricks. Int J Mol Sci 20(20)

    Google Scholar 

  • Bhattacharya R et al (2005) Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Kruppel-like factor KLF2. J Biol Chem 280(32):28848–28851

    Article  CAS  Google Scholar 

  • Cabral-Pacheco GA et al (2020) The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21(24)

    Google Scholar 

  • Checchi V et al (2020) The role of matrix metalloproteinases in periodontal disease. Int J Environ Res Public Health 17(14)

    Google Scholar 

  • Chen GH et al (2019) The molecular mechanism of EPO regulates the angiogenesis after cerebral ischemia through AMPK-KLF2 signaling pathway. Crit Rev Eukaryot Gene Expr 29(2):105–112

    Article  Google Scholar 

  • Chiu YL et al (2020) Ginkgo biloba induces thrombomodulin expression and tissue-type plasminogen activator secretion via the activation of Kruppel-like factor 2 within endothelial cells. Am J Chin Med 48(2):357–372

    Article  CAS  Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867

    Article  CAS  Google Scholar 

  • Cui N, Hu M, Khalil RA (2017) Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci 147:1–73

    Article  CAS  Google Scholar 

  • Das H et al (2006) Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci U S A 103(17):6653–6658

    Article  CAS  Google Scholar 

  • Das M et al (2012) Kruppel-like factor 2 (KLF2) regulates monocyte differentiation and functions in mBSA and IL-1beta-induced arthritis. Curr Mol Med 12(2):113–125

    Article  CAS  Google Scholar 

  • Das M et al (2019a) Induction of Kruppel-like factor 2 reduces K/BxN serum-induced arthritis. J Cell Mol Med 23(2):1386–1395

    Article  CAS  Google Scholar 

  • Das M et al (2019b) Myeloid Kruppel-like factor 2 critically regulates K/BxN serum-induced arthritis. Cell 8(8)

    Google Scholar 

  • Deem TL, Cook-Mills JM (2004) Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species. Blood 104(8):2385–2393

    Article  CAS  Google Scholar 

  • dela Paz NG et al (2012) Role of shear-stress-induced VEGF expression in endothelial cell survival. J Cell Sci 125(Pt 4):831–843

    Google Scholar 

  • El-Hashim AZ et al (2012) Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-kappaB-dependent pathways. Br J Pharmacol 166(6):1964–1976

    Article  CAS  Google Scholar 

  • Evrard SM et al (2016) Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun 7:11853

    Article  CAS  Google Scholar 

  • Franco C et al (2017) Matrix metalloproteinases as regulators of periodontal inflammation. Int J Mol Sci 18(2)

    Google Scholar 

  • Galvez BG et al (2001) Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling. J Biol Chem 276(40):37491–37500

    Article  CAS  Google Scholar 

  • Gimbrone MA Jr, Garcia-Cardena G (2013) Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 22(1):9–15

    Article  CAS  Google Scholar 

  • Govindaraju P et al (2019) CD44-dependent inflammation, fibrogenesis, and collagenolysis regulates extracellular matrix remodeling and tensile strength during cutaneous wound healing. Matrix Biol 75–76:314–330

    Article  Google Scholar 

  • Heiss C, Rodriguez-Mateos A, Kelm M (2015) Central role of eNOS in the maintenance of endothelial homeostasis. Antioxid Redox Signal 22(14):1230–1242

    Article  CAS  Google Scholar 

  • Hiroi T et al (2009) Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Kruppel-like transcription factors. Arterioscler Thromb Vasc Biol 29(10):1587–1593

    Article  CAS  Google Scholar 

  • Huo N et al (2002) MMP-7 (matrilysin) accelerated growth of human umbilical vein endothelial cells. Cancer Lett 177(1):95–100

    Article  CAS  Google Scholar 

  • Iivanainen E et al (2003) Endothelial cell-matrix interactions. Microsc Res Tech 60(1):13–22

    Article  CAS  Google Scholar 

  • Jha P, Das H (2017) KLF2 in regulation of NF-kappaB-mediated immune cell function and inflammation. Int J Mol Sci 18(11)

    Google Scholar 

  • Koo BH et al (2010) Thrombin-dependent MMP-2 activity is regulated by heparan sulfate. J Biol Chem 285(53):41270–41279

    Article  CAS  Google Scholar 

  • Kumar A et al (2011) p53 impairs endothelial function by transcriptionally repressing Kruppel-like factor 2. Arterioscler Thromb Vasc Biol 31(1):133–141

    Article  CAS  Google Scholar 

  • Laha D, Deb M, Das H (2019) KLF2 (kruppel-like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy. Autophagy 15(12):2063–2075

    Article  CAS  Google Scholar 

  • Larochelle C, Alvarez JI, Prat A (2011) How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett 585(23):3770–3780

    Article  CAS  Google Scholar 

  • Laronha H et al (2020) Challenges in matrix metalloproteinases inhibition. Biomolecules 10(5)

    Google Scholar 

  • Lee DY et al (2012) Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow. Proc Natl Acad Sci U S A 109(6):1967–1972

    Article  CAS  Google Scholar 

  • Lee GH et al (2020) Betulinic acid induces eNOS expression via the AMPK-dependent KLF2 signaling pathway. J Agric Food Chem 68(49):14523–14530

    Article  CAS  Google Scholar 

  • Levick SP et al (2011) Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 89(1):12–19

    Article  CAS  Google Scholar 

  • Lin Z et al (2006) Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation. Arterioscler Thromb Vasc Biol 26(5):1185–1189

    Article  CAS  Google Scholar 

  • Lin Z et al (2010) Kruppel-like factor 2 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol 30(10):1952–1959

    Article  CAS  Google Scholar 

  • Liu J et al (2006) Wild-type p53 inhibits nuclear factor-kappaB-induced matrix metalloproteinase-9 promoter activation: implications for soft tissue sarcoma growth and metastasis. Mol Cancer Res 4(11):803–810

    Article  CAS  Google Scholar 

  • Loghmani H, Conway EM (2018) Exploring traditional and nontraditional roles for thrombomodulin. Blood 132(2):148–158

    Article  CAS  Google Scholar 

  • Lozito TP, Tuan RS (2012) Endothelial cell microparticles act as centers of matrix metalloproteinsase-2 (MMP-2) activation and vascular matrix remodeling. J Cell Physiol 227(2):534–549

    Article  CAS  Google Scholar 

  • Maity J et al (2020) KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism. Redox Biol 36:101622

    Article  CAS  Google Scholar 

  • Meyer E et al (2005) Matrix metalloproteinases 9 and 10 inhibit protein kinase C-potentiated, p53-mediated apoptosis. Cancer Res 65(10):4261–4272

    Article  CAS  Google Scholar 

  • Moccia F et al (2019) Endothelial ca(2+) signaling, angiogenesis and vasculogenesis: just what it takes to make a blood vessel. Int J Mol Sci 20(16)

    Google Scholar 

  • Montero I et al (2006) C-reactive protein induces matrix metalloproteinase-1 and -10 in human endothelial cells: implications for clinical and subclinical atherosclerosis. J Am Coll Cardiol 47(7):1369–1378

    Article  CAS  Google Scholar 

  • Moore CS, Crocker SJ (2012) An alternate perspective on the roles of TIMPs and MMPs in pathology. Am J Pathol 180(1):12–16

    Article  CAS  Google Scholar 

  • Nakajima H, Mochizuki N (2017) Flow pattern-dependent endothelial cell responses through transcriptional regulation. Cell Cycle 16(20):1893–1901

    Article  CAS  Google Scholar 

  • Nathan C (2002) Points of control in inflammation. Nature 420(6917):846–852

    Article  CAS  Google Scholar 

  • Newby AC (2005) Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 85(1):1–31

    Article  CAS  Google Scholar 

  • Nicoli S et al (2010) MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464(7292):1196–1200

    Article  CAS  Google Scholar 

  • Niedzielski M et al (2020) New possible pharmacological targets for statins and ezetimibe. Biomed Pharmacother 129:110388

    Article  CAS  Google Scholar 

  • Nissinen L, Kahari VM (2014) Matrix metalloproteinases in inflammation. Biochim Biophys Acta 1840(8):2571–2580

    Article  CAS  Google Scholar 

  • Niu N et al (2019) Targeting mechanosensitive transcription factors in atherosclerosis. Trends Pharmacol Sci 40(4):253–266

    Article  CAS  Google Scholar 

  • Novodvorsky P, Chico TJ (2014) The role of the transcription factor KLF2 in vascular development and disease. Prog Mol Biol Transl Sci 124:155–188

    Article  CAS  Google Scholar 

  • Olejarz W, Lacheta D, Kubiak-Tomaszewska G (2020) Matrix metalloproteinases as biomarkers of atherosclerotic plaque instability. Int J Mol Sci 21(11)

    Google Scholar 

  • Oviedo-Orta E et al (2008) Comparison of MMP-2 and MMP-9 secretion from T helper 0, 1 and 2 lymphocytes alone and in coculture with macrophages. Immunology 124(1):42–50

    Article  CAS  Google Scholar 

  • Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4(8):617–629

    Article  CAS  Google Scholar 

  • Pathak R et al (2014) IKKbeta regulates endothelial thrombomodulin in a Klf2-dependent manner. J Thromb Haemost 12(9):1533–1544

    Article  CAS  Google Scholar 

  • Posma JJ, Posthuma JJ, Spronk HM (2016) Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 14(10):1908–1916

    Article  CAS  Google Scholar 

  • Pozzi A, Yurchenco PD, Iozzo RV (2017) The nature and biology of basement membranes. Matrix Biol 57–58:1–11

    Article  Google Scholar 

  • Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG (2020) Metalloproteinases and their inhibitors: potential for the development of new therapeutics. Cell 9(5)

    Google Scholar 

  • Rempe RG, Hartz AMS, Bauer B (2016) Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab 36(9):1481–1507

    Article  CAS  Google Scholar 

  • Rempe RG et al (2018) Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J Neurosci 38(18):4301–4315

    Article  CAS  Google Scholar 

  • Rohani MG, Parks WC (2015) Matrix remodeling by MMPs during wound repair. Matrix Biol 44–46:113–121

    Article  Google Scholar 

  • Rolph DN et al (2018) Ferutinin directs dental pulp-derived stem cells towards the osteogenic lineage by epigenetically regulating canonical Wnt signaling. Biochim Biophys Acta Mol basis Dis

    Google Scholar 

  • Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9(2):267–285

    Article  CAS  Google Scholar 

  • Sako K et al (2009) Angiopoietin-1 induces Kruppel-like factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. J Biol Chem 284(9):5592–5601

    Article  CAS  Google Scholar 

  • SenBanerjee S et al (2004) KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med 199(10):1305–1315

    Article  CAS  Google Scholar 

  • Serra R (2020) Matrix metalloproteinases in health and disease. Biomol Ther 10(8)

    Google Scholar 

  • Sheu BC et al (2001) A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res 61(1):237–242

    CAS  Google Scholar 

  • Shi H et al (2013) Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function. Am J Physiol Heart Circ Physiol 304(6):H796–H805

    Article  CAS  Google Scholar 

  • Shin JW et al (2019) Molecular mechanisms of dermal aging and antiaging approaches. Int J Mol Sci 20(9)

    Google Scholar 

  • Song J et al (2020) Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells. Biochem Biophys Res Commun 525(3):812–818

    Article  CAS  Google Scholar 

  • Taraboletti G et al (2002) Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 160(2):673–680

    Article  CAS  Google Scholar 

  • Tian R et al (2019) Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2. Biochim Biophys Acta Mol basis Dis 1865(6):1701–1712

    Article  CAS  Google Scholar 

  • Turpaev KT (2020) Transcription factor KLF2 and its role in the regulation of inflammatory processes. Biochemistry (Mosc) 85(1):54–67

    Article  CAS  Google Scholar 

  • Vacek TP et al (2015) Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vasc Health Risk Manag 11:173–183

    Article  Google Scholar 

  • Van den Steen PE et al (2000) Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96(8):2673–2681

    Article  Google Scholar 

  • Wang X, Khalil RA (2018) Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 81:241–330

    Article  CAS  Google Scholar 

  • Wang W et al (2010) Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS. Blood 115(14):2971–2979

    Article  CAS  Google Scholar 

  • Wang D et al (2017) AMPK-KLF2 signaling pathway mediates the proangiogenic effect of erythropoietin in endothelial colony-forming cells. Am J Physiol Cell Physiol 313(6):C674–C685

    Article  Google Scholar 

  • Wolf D, Ley K (2019) Immunity and inflammation in atherosclerosis. Circ Res 124(2):315–327

    Article  CAS  Google Scholar 

  • Wu C et al (2013) Abeta(1-42) disrupts the expression and function of KLF2 in Alzheimer’s disease mediated by p53. Biochem Biophys Res Commun 431(2):141–145

    Article  CAS  Google Scholar 

  • Yang CC et al (2018) Galangin inhibits thrombin-induced MMP-9 expression in SK-N-SH cells via protein kinase-dependent NF-kappaB phosphorylation. Int J Mol Sci 19(12)

    Google Scholar 

  • Zhuang T et al (2019) Endothelial Foxp1 suppresses atherosclerosis via modulation of Nlrp3 Inflammasome activation. Circ Res 125(6):590–605

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by National Institutes of Health grants, R01AR068279 (NIAMS), STTR R42EY031196 (NEI), and STTR 1R41AG057242 (NIA). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA

    Sarah Anderson, Derek Barthels & Hiranmoy Das

Authors
  1. Sarah Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Derek Barthels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiranmoy Das
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiranmoy Das .

Editor information

Editors and Affiliations

  1. Laboratory of Molecular Pharmacology Department of Pharmacy, University of Patras, Patras, Greece

    Evangelia Papadimitriou

  2. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, USA

    Constantinos M. Mikelis

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Anderson, S., Barthels, D., Das, H. (2023). Kruppel-Like Factor 2 and Matrix Metalloproteinases in the Context of Vasculature. In: Papadimitriou, E., Mikelis, C.M. (eds) Matrix Pathobiology and Angiogenesis. Biology of Extracellular Matrix, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-031-19616-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation