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Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that β1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of β1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to β1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated “shear-stress-like” phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of β1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.

Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGF xxx and VEGF xxx b families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGF xxx splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described. The role of VEGF xxx b isoforms is less well known, but they have been shown to inhibit VEGF xxx -mediated angiogenesis, while being partial or weak activators of VEGFR receptors in endothelial cells. On the opposite, their role on tumor cells expressing VEGFRs at their surface remains largely unknown. In this study, we find elevated levels of VEGF 165 b, the main VEGF xxx b isoform, in 36% of non-small cell lung carcinoma (NSCLC), mainly lung adenocarcinoma (46%), and show that a high VEGF 165 b/VEGF 165 ratio correlates with the presence of lymph node metastases. At the molecular level, we demonstrate that VEGF 165 b stimulates proliferation and invasiveness of two lung tumor cell lines through a VEGFR/β1 integrin loop. We further provide evidence that the isoform-specific knockdown of VEGF 165 b reduces tumor growth, demonstrating a tumor-promoting autocrine role for VEGF 165 b in lung cancer cells. Importantly, we show that bevacizumab, an anti-angiogenic compound used for the treatment of lung adenocarcinoma patients, increases the expression of VEGF 165 b and activates the invasive VEGFR/β1 integrin loop. Overall, these data highlight an unexpected role of the VEGF 165 b splice variant in the progression of lung tumors and their response to anti-angiogenic therapies.

Cerebral cavernous malformation (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM disease is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells expanded in vitro enter into senescence-associated secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the cytoskeletal, molecular and transcriptomic disorders provoked by ROCK dysfunctions. By this, we propose that CCM2 and ROCK could be parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of ageing by cellular mechanics. These in vitro findings reconcile the known dysregulated traits of CCM2-deficient endothelial cells into a unique endothelial fate. Based on these in vitro results, we propose that a SASP could link the increased ROCK-dependent cell contractility in CCM2-deficient endothelial cells with microenvironment remodelling and long-range chemo-attraction of endothelial and immune cells.

Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGF and VEGF b families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGF splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described. The role of VEGF b isoforms is less well known, but they have been shown to inhibit VEGF -mediated angiogenesis, while being partial or weak activators of VEGFR receptors in endothelial cells. On the opposite, their role on tumor cells expressing VEGFRs at their surface remains largely unknown. In this study, we find elevated levels of VEGF b, the main VEGF b isoform, in 36% of non-small cell lung carcinoma (NSCLC), mainly lung adenocarcinoma (46%), and show that a high VEGF b/VEGF ratio correlates with the presence of lymph node metastases. At the molecular level, we demonstrate that VEGF b stimulates proliferation and invasiveness of two lung tumor cell lines through a VEGFR/β1 integrin loop. We further provide evidence that the isoform-specific knockdown of VEGF b reduces tumor growth, demonstrating a tumor-promoting autocrine role for VEGF b in lung cancer cells. Importantly, we show that bevacizumab, an anti-angiogenic compound used for the treatment of lung adenocarcinoma patients, increases the expression of VEGF b and activates the invasive VEGFR/β1 integrin loop. Overall, these data highlight an unexpected role of the VEGF b splice variant in the progression of lung tumors and their response to anti-angiogenic therapies.

Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that beta 1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of beta 1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to beta 1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated \"shear-stress-like\" phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of beta 1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.

Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that b1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of b1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to b1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated ''shear-stress-like'' phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of b1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.

Abstract Cerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM diseases is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells enter into senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions. By this, we identify CCM1/2 and ROCKs as parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of aging by cellular mechanics. This discovery reconciles the dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent endothelial fate that links perturbed mechanics to microenvironment remodelling and long-range activation of endothelial and immune cells. Competing Interest Statement The authors have declared no competing interest.

The photodegradation of the S(+)- and R(−)-ketoprofen (KP) enantiomers in the bovine serum albumin matrix was studied by steady-state photolysis with the use of λirr > 320 nm and transient absorption spectroscopy with λexc = 355 nm, at 1/1 and 2/1 KP/BSA molar ratios. R(−)-KP was found to be more labile than S(+). Triplet ketoprofen species were evidenced with lifetimes of 400 ns for S(+) and 600 ns for R(−)-KP. Further longer-lived transients with lifetimes of 2.6 and 6.0 μs for S(+) and R(−), respectively, were detected. On the basis of the binding constants of the drug enantiomers to the two main binding sites of the protein, obtained from circular dichroism experiments, the individual disappearance quantum yields of the 1:1 and 2:1 diastereomeric KP:BSA complexes could be estimated. The photoreactivity in the BSA matrix was rationalized on the basis of diastereoselective photodecarboxylation in the two main protein sites.