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Role of Krüppel-Like Factors in Endothelial Cell Function and Shear Stress–Mediated Vasoprotection
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Angiogenesis is a complex process that involves multiple gene products expressed by different cell types and recapitulates many of the molecular events that occur during vascular development. Imbalance of this process results in malignant and ischemic disorders [104]. The effect of shear stress on angiogenesis is not well described; most of the expected effects are extrapolated from the pattern of growth factors, such as VEGF, induced by in vitro shear stress experiments. Studies from our laboratory demonstrate that KLF2 potently inhibits VEGF-mediated angiogenesis [31]. In the nude mouse ear model of angiogenesis, KLF2 potently inhibits permeability, tissue edema, and angiogenesis. From a mechanistic standpoint, KLF2 inhibits cell proliferation, VEGFR2 expression, and VEGF-induced endothelial activation (characterized by reduction of calcium influx and suppression of VCAM-1, TF, and cyclooxygenase 2) [31]. KLF2 has been shown to regulate VEGFR2 (also referred as to FMS-like tyrosine kinase 1 [Flt1] or kinase insert domain receptor [KDR]) by cooperating with Ets during vascular development in Xenopus embryos [105].
Investigation of angiogenesis genes with anterior cruciate ligament rupture risk in a South African population
Published in Journal of Sports Sciences, 2018
Masouda Rahim, Hayden Hobbs, Willem van der Merwe, Michael Posthumus, Malcolm Collins, Alison V. September
The angiogenesis pathway is regulated by several growth factors and cytokines; principally VEGF (Ferrara, Gerber, & LeCouter, 2003). In particular, the A isoform of this protein, encoded by VEGFA, is considered to be the most potent. Kinase insert-domain receptor (KDR), encoded by the KDR gene, is the main signalling receptor for VEGFA and mediates the mitogenic and chemotactic actions of the ligand (Ferrara et al., 2003).
Risk modelling further implicates the angiogenesis pathway in anterior cruciate ligament ruptures
Published in European Journal of Sport Science, 2022
Masouda Rahim, Miguel Lacerda, Malcolm Collins, Michael Posthumus, Alison V. September
Ligaments are metabolically active tissues which are able to respond to stimuli, primarily mechanical load, however, the rate of metabolism is slow (Wang, 2006). Previous research has shown the metabolic rate within the ligament may increase in response to mechanical loading to allow for remodelling of the extracellular matrix (Wang, 2006). For example, studies have demonstrated an increase in the expression of several cell signalling molecules (Jiang et al., 2012; Thampatty et al., 2007; Yang, Im, & Wang, 2005) after the application of mechanical stimuli; though the precise mechanotransduction mechanisms involved remain to be elucidated (Wang, 2006). A number of studies have also reported a pro-angiogenic expression profile after cyclic strain of tenocytes (Mousavizadeh et al., 2014; Petersen et al., 2004) in tendons and during remodelling (Egginton, 2009). Vascular endothelial growth factor (VEGF) is an essential regulator of angiogenesis, with the A isoform, encoded by VEGFA, believed to have the highest angiogenic potency. Most of the mitogenic, angiogenic and permeability-enhancing effects of VEGFA are mediated via its receptor kinase insert-domain receptor (KDR), encoded by KDR (Ferrara, Gerber, & LeCouter, 2003). The interactions between VEGF and its receptor are essential for many angiogenic processes both in normal physiology and pathological processes (Carmeliet, 2003). Previous studies have described independent and haplotype associations within the VEGFA and KDR genes with risk susceptibility to ACL ruptures (Rahim et al., 2014; Rahim et al., 2018) and Achilles tendinopathy (Rahim et al., 2016); highlighting the angiogenesis signalling pathway as a potential contributor to musculoskeletal soft tissue injuries. The angiogenesis signalling pathway is a component of the more complex matrix remodelling pathway and is regulated by a myriad of growth factors, cytokines and signalling factors (Egginton, 2009; Petersen et al., 2003; Petersen et al., 2004) as well as extrinsic factors such as mechanical loading (Egginton, 2009; Mousavizadeh et al., 2014; Petersen et al., 2004). For this reason it is important to explore the angiogenesis signalling pathway within the broader ECM remodelling pathway network. Two interleukins (ILs), namely IL-1β and IL-6, as well as the interleukin-6 receptor which function as modulators of the angiogenesis signalling pathway (Figure 1) were therefore selected to be included in a model to identify the key genetic markers that could potentially be used to help identify an individual’s genetic predisposition to ACL rupture risk, thereby adding to our understanding of the biological mechanisms that contribute to these injuries.