Mechanical Regulation of the Proangiogenic Factor CCN1/CYR61 Gene Requires the Combined Activities of MRTF-A and CREB-binding Protein Histone Acetyltransferase

Abstract

The cellular components of the cardiovascular, digestive, and urinary systems elicit adaptive responses to mechanical/pressure overload acutely by retooling their cytoskeletal structures (i.e. increasing actin polymerization rate and contractile protein levels) and chronically by remodeling their extracellular environment. These compensatory responses are associated with the activation of angiogenesis to meet increased metabolic demands and improve tissue perfusion (1, 2). In the absence of angiogenesis, hypertrophic growth increases diffusion distance around microvessels resulting in reduced oxygen supply and hypoxia, altered muscle contractility, and organ failure. Clearly, an unsatisfactory/ insufficient vascularization is an important restraint on the adaptive capabilities of mechanically overloaded tissues.Neovascularization in mechanically challenged smooth muscle-rich organs in particular is promoted by various mechanoresponsive angiogenic factors including CCN1, formerly known as cysteine-rich protein 61 (Cyr61), a functionally multifaceted matricellular protein that appears in the extracellular environment particularly during development and pathological states (3, 4). The CCN1 protein acts either independently or in concert with vascular endothelial growth factor to drive sprouting and branching of new blood vessels and provides protection against oxidative stress (5, 6). Essentially, the CCN1 protein enhances angiogenesis by providing structural integrity to blood vessels, supplying necessary growth factors for endothelial and perivascular cells, and modulating extracellular matrix synthesis and degradation. Targeted disruption of the CCN1 gene leads to early or perinatal lethality in mice due to impaired vessel formation and/or branching (7). The CCN1 proangiogenic properties have further been demonstrated in different models of angiogenesis including rabbit ischemic hind limb and rat cornea models in which CCN1 improves angiogenesis and collateral blood flow to an even larger extent than vascular endothelial growth factor (8, 9).Mechanical strain typified by tension, stretch, shear, and pressure largely controls the expression of the CCN1 gene, although little is known about the molecular mechanisms involved (10). CCN1 was induced in mechanically stimulated myocardial fibroblasts and in smooth muscle cells (SMCs) 2 2 h

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

“…These findings suggest that SRF is not involved in CTGF regulation by stretch in MC. MRTF-A, although not assessed for CTGF (also known as CCN2), was found to regulate stretch-induced increases in the related gene CCN1 (Hanna et al, 2009). Our data, however, show that MRTF-A siRNA did not inhibit CTGF upregulation by stretch (Fig.…”

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…At the cellular level this response involves endothelial sprouting via CCN1 (CYR61) 29 and maturation-that is, pericyte investment-via CCN2 (CTGF) 24 resulting in a stable and functional vascular network that can carry collateral blood flow and improve conductance. Pericyte investment is crucial herein since Ang 2, by virtue of disrupting pericyte investment 38 , abolished the positive effects exerted by T 4-MRTF signalling (Fig.…”

“…1f) 28 . Both, MRTF-A and T 4, induced expression of genes involved in microvessel growth, most notably CCN1, mediating angiogenesis 29 and CCN2, relevant for 10T1/2 pericyte-like cell attraction 24 ( Supplementary Fig. 1c-g).…”

Cyr61, a Matricellular Protein, Is Needed for Dendritic Arborization of Hippocampal Neurons

“…Another line of reasoning derives from known mTOR links to some cyr61 transcription regulators. The transcription factors involved in the control of cyr61 expression in various cellular models include TCF4 (26), SRF (62), CBP (62), CREB (63), FOXO3a (64), AP1 (27,63), STAT3 (65), and HIF1␣ (27). The most obvious link is HIF1␣, known as an mTOR effector induced under hypoxic conditions (9).…”