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Vascular remodelling

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Hunt for the culprit of cardiovascular injury in kidney disease

Faul, Christian, Cardiovasc Res (2015) 108(2) doi: 10.1093/cvr/cvv228 - Click here to view the abstract

Hypotheses on how α-klotho deficiency promotes arterial calcification in chronic kidney disease. Under Hypothesis 1, vascular expression of the transmembrane form of α-klotho, which is most highly expressed in the kidney, protects vessels from calcification such that deficiency of vascular α-klotho in chronic kidney disease induces calcification directly. The report by Mencke et al. (Cardiovasc Res. 2015;108(2):220-31) contradicts this hypothesis. Under Hypothesis 2, reduced circulating levels of the soluble form of α-klotho, which is released into circulation from ectodomain shedding of renal transmembrane α-klotho, render vessels susceptible to calcification. This hypothesis was not tested by Mencke et al. Based on an extensive body of prior in vitro, animal and human data, hyperphosphatemia is likely an independent causal factor in the pathogenesis of arterial calcification in chronic kidney disease (central panel). Under this model, concomitant deficiencies of the transmembrane and soluble forms of α-klotho in chronic kidney disease are indirectly associated with calcification.

Platelets and thromboxane receptors: pivotal players in arteriogenesis

Van Hinsbergh, Victor W. M, Cardiovasc Res (2015) 107(4) doi: 10.1093/cvr/cvv194 - Click here to view the abstract



Involvement of platelets and TPs in arteriogenesis in mice.6,7 After femoral occlusion, altered shear forces and oxygen availability modulate endothelial functioning, after which platelets start adhering the endothelium of pre-existing collaterals and vessels that became ischaemic distal of the occlusion. These platelets expose P-selectin and can release many factors, including VEGF-A and SDF-1, but do not form occluding thrombi. In animals deficient of TP-α, platelet interaction and subsequent arteriogenesis is inhibited. Platelet binding requires GPIbα6 which interacts with endothelial vWF under high shear forces, and P-selectin, which can bind to PSGL1 on leucocytes and activated endothelium. Subsequently, these platelets interact and facilitate the binding and influx of VEGFR1- and CXCR4-bearing monocytes into the vessel wall. The invaded cells subsequently contribute in orchestrating the arteriogenic process.

Emerging translational approaches to target STAT3 signalling and its impact on vascular disease

Dutzmann, Jochen, Cardiovasc Res (2015) 106(3) doi: 10.1093/cvr/cvv103 - Click here to view the abstract


Physiological regulation and pharmacological inhibition of the STAT3 signalling pathway. STAT3 is a key player in cell signalling and transcription in response to a wide range of stimuli and in various ways. The most relevant STAT3 signalling pathways in vascular diseases are indicated with continuous lines; less well-investigated STAT3 signalling pathways are indicated with broken lines. GTP, guanosine triphosphate; JAK, janus kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; miRNA, microRNA; NFκB, nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells; P, phosphate residue; PIAS3, protein inhibitor of activated STAT; PLC-γ2, phospholipase C, γ2 isoform; PTP, protein tyrosine phosphatase; SOCS3, suppressor of cytokine signalling; Syk, spleen tyrosine kinase; TF, transcription factor.

Emerging translational approaches to target STAT3 signalling and its impact on vascular disease

Dutzmann, Jochen, Cardiovasc Res (2015) 106(3) doi: 10.1093/cvr/cvv103 - Click here to view the abstract


STAT3 in vascular diseases. STAT3 is shown to be activated in response to mitogenic stimuli in different cell types in vitro, in in vivo models of numerous vascular diseases, and in patients suffering from cardiovascular diseases. STAT3 activation causes functional changes in most cell types, leading to a more undifferentiated and activated phenotype and thereby contributing to vascular lesion formation.

Stimulating arteriogenesis but not atherosclerosis: IFN-alpha/beta receptor subunit 1 as a novel therapeutic target

Cochain, Clement;, Cardiovasc Res (2015) 107(2) doi: 10.1093/cvr/cvv174 - Click here to view the abstract


After arterial occlusion, arteriogenesis promotes blood perfusion recovery, hence alleviating tissue ischaemia. Some anti-atherogenic cytokines (e.g. IL-10) inhibit arteriogenesis, whereas some pro-arteriogenic strategies (bone marrow mononuclear cell infusion and CCL2 administration) promote atherosclerotic plaque growth. IFN-β was shown to inhibit arteriogenesis and to promote atherosclerosis. Teunissen et al. (Cardiovasc Res. 2015;107(2):255-66) have now provided evidence that a mAb-based therapeutic strategy blocking IFNAR1, the receptor of IFN-β and IFN-α, promotes arteriogenesis and blood perfusion recovery after hindlimb ischaemia, while having no effects on atherosclerotic plaque growth.

Biomechanical factors as triggers of vascular growth

Hoefer, Imo E, Cardiovasc Res (2013) 99(2) doi: 10.1093/cvr/cvt089 - Click here to view the abstract

Vessels are subjected to three different forms of stresses: shear stress τ, circumferential stress σθ, and axial stress σz. Shear stress depends on flow (Q), blood viscosity (η), and vessel radius (r). Circumferential stress is defined by the pressure (p) acting on the vascular wall, vessel radius (r), and the height (h) of the vessel wall. The force (F) that longitudinally acts on the vessel and the cross-sectional area of the vessel wall (A) are the determinants for axial stress, which leads to adaptations in vessel length.

Biomechanical factors as triggers of vascular growth

Hoefer, Imo E, Cardiovasc Res (2013) 99(2) doi: 10.1093/cvr/cvt089 - Click here to view the abstract


Flow and shear patterns in different parts of the vascular tree. The inner curvature of curved arteries is usually subjected to low shear stress (blue), whereas the outer curvature experiences higher shear stress (purple). In regions, where vessels branch or bifurcate, turbulent flow (orange), or combinations of low and turbulent flow (spotted parts) depending on vessel diameter and angle can occur. High shear generally protects from atherosclerosis, whereas low shear and turbulent flow may lead to wall thickening and atherosclerotic plaque formation.

A TRPC3 signalling complex promotes cerebral artery remodelling during hypertension

Pires, Paulo Wagner, Cardiovasc Res (2016) 109(1) doi: 10.1093/cvr/cvv261 - Click here to view the abstract

Hypothesized signalling pathway for the involvement of TRPC3 in hypertensive inward remodelling of cerebral arteries. Chronic Ang II hypertension induces hypertensive inward hypertrophic remodelling of cerebral arteries through increased expression of TRPC3 channels. Tonically active TRPC3 channels conduct both Na+ and Ca2+ ions, albeit the small fractional Ca2+ component of this current is likely not sufficient to directly activate PKC. However, inflow of Na+ may cause membrane depolarization that opens voltage-gated Ca2+ channels, leading to a larger Ca2+ influx (1). It is also possible that localized increases in intracellular Na+ may induce the NCX to operate in reverse mode, resulting in Ca2+ influx (2) and removing Na+, thus maintaining electrical gradients favouring Ca2+ influx. Activated PKC phosphorylates ADAM17, which cleaves Pro-Hb-EGF, releasing free EGF that binds to EGFR, and leads to transactivation. Chronic EGFR activation then leads to smooth muscle cell proliferation and inward hypertrophic remodelling of cerebral arteries.

Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1-NOTCH interactions

Peacock, Hanna M., Cardiovasc Res (2016) 109(2) doi: 10.1093/cvr/cvv264 - Click here to view the abstract

Alk1 knockout phenotype appears during vascular remodelling, concurrent with onset of blood flow and expression of Alk1 and Bmp10. The initial capillary plexus of the mouse embryo yolk sac forms between embryonic day (E) 7.5 and E8.5. The heart begins to beat at E8.0, but initially only plasma is flowing through the capillaries, while the erythroblasts are confined to the blood islands of the yolk sac. At E8.5, erythroblasts are released into circulation, marking the beginning of true blood flow. At the same time, vascular remodelling is initiated, and Bmp10 and Alk1 begin to be expressed. Vascular remodelling is completed by E10.5, at which point Bmp9 begins to be expressed. The phenotype of Alk1 knockout mice arises from E8.5 to E9.5 as a failure of vascular remodelling.

Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1-NOTCH interactions

Peacock, Hanna M., Cardiovasc Res (2016) 109(2) doi: 10.1093/cvr/cvv264 - Click here to view the abstract


HHT-related AVMs occur through endothelial cell proliferation, while idiopathic AVMs may occur through endothelial cell hypertrophy. AVMs arise through the enlargement of a capillary into a direct shunt between the artery and vein. In HHT, we propose that loss of ALK1 may lead to decreased NOTCH signalling through impaired TMEM100 and ID1/3 expression and functioning. A decrease in NOTCH signalling permits cellular proliferation and hence enlargement of the capillary into the AVM. In some idiopathic AVMs, there is elevated NOTCH signalling, which leads to cellular hypertrophy and enlargement of the capillary into an AVM.

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