Vascular ligation response is independent of p107: stressing the role of the related p130

2003 ◽  
Vol 285 (2) ◽  
pp. H915-H918 ◽  
Author(s):  
Jürgen R. Sindermann ◽  
Christiane Köbbert ◽  
Florian Bauer ◽  
Adriane Skaletz-Rorowski ◽  
Helge Hohage ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Injury ◽  
Femoral Artery ◽  
Arterial Injury ◽  
Injury Response ◽  
Artery Ligation ◽  
Wall Area ◽  
Carotid Artery Ligation ◽  
Electric Injury

Recent studies have revealed the role of the pRb family members pRb and p130 in the response to vascular injury. We evaluated the arterial injury response in the absence of p107, a protein that shares a high degree of homology with the injury-controlling p130. Carotid artery ligation and perivascular electric injury of the femoral artery were applied to p107 knockout (p107 –/–) mice, and morphometric analysis was performed 3 wk after ligation and electric injury. Arterial vessels of p107 –/– mice were indistinguishable from controls under basal conditions. After carotid artery ligation the p107 –/– mice ( n = 7) did not display an enhanced ligation response compared with controls ( n = 9), which was studied over a distance of ∼450 μm proximal and ∼200 μm distal from the ligation site, with regard to vessel wall area, neointima area, and lumen area. Corresponding with this, morphometric data obtained from the perivascular electric injury of the femoral artery confirmed the lack of enhanced ligation and injury response in the absence of p107. We conclude that the pRb family member p107 is not a key regulator in vascular injury response. These data, in conjunction with previously reported results, indicate that the control of vascular injury response is not a redundant feature of pRb proteins but primarily specific for p130. Further studies on functional domains of p130 and p107 will help to resolve the pathways in vascular injury response.

Abstract 160: Tuberosis Sclerosis Complex 1 Mediated Neointima Formation and Arterial Thrombosis Following Vascular Injury

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Eo Jin Kim ◽  
Yong-Joo Ahn ◽  
Maya Hwewon Kim ◽  
Hyung-Hwan Kim
Keyword(s):  
Smooth Muscle ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Knockout Mice ◽  
Arterial Thrombosis ◽  
Immunoblot Analysis ◽  
Arterial Injury ◽  
Conditional Knockout ◽  
Neointima Formation

Objectives: Vascular injury and thrombosis are main leading causes of cardiovascular diseases. Tuberous sclerosis complex (TSC) is a genetic disorder caused by heterozygous mutations in either of two genes, TSC1 and TSC2. Although role of TSCs has been implicated in cardiovascular diseases, the tissue- and isoform-specific roles of TSCs in the vascular response to injury are not known. Methods and Results: To determine the role of TSC1 in arterial injury and thrombosis, we generated vascular smooth muscle cell-specific TSC1 conditional knockout mice (TSC1SM22-/-) by crossing vascular smooth muscle cell-specific Cre (SM22Cre) mice with TSC1flox/flox mice and performed carotid artery ligation in haploinsufficient TSC1 conditional knockout mice (TSC1SM22+/-) compared with that of WT or haploinsufficient TSC2 knockout mice (TSC2+/-). Acute carotid artery occlusion was investigated by 5% ferric chloride injury. Arterial thrombosis and neointima formation were measured at 14 days after arterial ligation. Expression of proteins was observed by immunoblot analysis. The neointima formation was significantly increased in TSC1SM22+/- mice (intimal thickness/medial thickness ratio; 1.14 ± 0.14, p<0.001) compared with that of WT mice (0.13 ± 0.03). Two weeks after arterial injury, arterial thrombus area was increased in TSC1SM22+/- mice (thrombus area/luminal area ratio; 72.1 ± 4.4, p<0.001) compared with that of WT mice (0.1 ± 0.0) but there are no significant effect in acute arterial thrombosis induced by ferric chloride. Loss of TSC1 and hyper-activation of mammalian target of rapamycin complex 1 including mTOR and S6 proteins were observed by immunoblot analysis of carotid artery tissue lysates of TSC1SM22+/- mice compared with that of WT. Conclusion: These findings suggest that regulation of TSC1 and mTOR might be useful for therapeutic intervention in vascular injury and thrombosis.

scholarly journals Gender-Specific Modulation of the Response to Arterial Injury by Soluble Guanylate Cyclase α1

2009 ◽  
Vol 3 (1) ◽  
pp. 98-104 ◽  
Author(s):  
Pieter Vermeersch ◽  
Emmanuel Buys ◽  
Patrick Sips ◽  
Peter Pokreisz ◽  
Glenn Marsboom ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Specific Effect ◽  
Arterial Injury ◽  
Brdu Incorporation ◽  
Artery Ligation ◽  
Targeted Deletion ◽  
Carotid Artery Ligation ◽  
Gender Specific

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of α and β subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1-/-), resulting in a non-functional heterodimer. Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1-/- mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively. Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1-/-. In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. 3H-thymidine incorporation in cultured sGCa1-/- smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1-/- M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1-/- M than in WT M mice (p<0,05 for both) but were not different in F mice. Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1-/- mice and a gender-specific effect on the adaptive response to vascular injury.

Vascular injury response in mice is dependent on genetic background

2006 ◽  
Vol 290 (3) ◽  
pp. H1307-H1310 ◽  
Author(s):  
Jürgen R. Sindermann ◽  
Christiane Köbbert ◽  
Adriane Skaletz-Rorowski ◽  
Günter Breithardt ◽  
Gabriele Plenz ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Genetic Background ◽  
Fold Increase ◽  
Arterial Injury ◽  
Neointima Formation ◽  
Genetic Modifiers ◽  
Injury Response ◽  
Wall Area ◽  
Injury Model ◽  
Vessel Wall Area

Mouse models are employed to unravel the pathophysiology of vascular restenosis. Although much effort has been spent on how to apply an adequate arterial injury, the influence of the genetic background of mice has not yet received sufficient consideration. The study presented herein was designed to demonstrate the influence of the mouse strain on vascular injury response. Mice of a defined background (50% 129 strain and 50% DBA strain) were backcrossed into either the 129 strain or the DBA strain. Male offspring were subjected to a femoral artery injury model by applying an electric current. Morphometric analysis revealed that backcrossing into the 129 strain resulted in a significant ( P < 0.001) 17-fold increase in neointima formation ( n = 17 mice) compared with backcrossing into the DBA strain ( n = 19). The values of neointima area were 9.18 × 103 ± 2.13 × 103 and 0.54 × 103 ± 0.39 × 103 μm2, respectively. In conjunction, the vessel wall area was enhanced by 1.8-fold ( P < 0.001). In contrast, no significant differences were found for the areas of the lumen and the tunica media. Similarly, a significant increase in neointima formation was also found for mice of pure 129 strain compared with pure DBA strain. The results underline the importance of the genetic background for studies on vascular injury response. Furthermore, because the mouse genome of the various strains is well defined, serial testing of the genetic background of mice will provide candidate genes and/or genetic modifiers controlling vascular injury response.

scholarly journals Inflammation and vascular smooth muscle cell dedifferentiation following carotid artery ligation

2017 ◽  
Vol 49 (3) ◽  
pp. 115-126 ◽  
Author(s):  
B. Paul Herring ◽  
April M. Hoggatt ◽  
Sarah L. Griffith ◽  
Jeanette N. McClintick ◽  
Patricia J. Gallagher
Keyword(s):  
Smooth Muscle ◽  
Carotid Artery ◽  
Smooth Muscle Cells ◽  
Vascular Injury ◽  
Carotid Arteries ◽  
Noncoding Rnas ◽  
Muscle Cells ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Reporter Mice

Following vascular injury medial smooth muscle cells dedifferentiate and migrate through the internal elastic lamina where they form a neointima. The goal of the current study was to identify changes in gene expression that occur before the development of neointima and are associated with the early response to injury. Vascular injury was induced in C57BL/6 mice and in Myh11-creER(T2) mTmG reporter mice by complete ligation of the left carotid artery. Reporter mice were used to visualize cellular changes in the injured vessels. Total RNA was isolated from control carotid arteries or from carotid arteries 3 days following ligation of C57BL/6 mice and analyzed by Affymetrix microarray and quantitative RT-PCR. This analysis revealed decreased expression of mRNAs encoding smooth muscle-specific contractile proteins that was accompanied by a marked increase in a host of mRNAs encoding inflammatory cytokines following injury. There was also marked decrease in molecules associated with BMP, Wnt, and Hedgehog signaling and an increase in those associated with B cell, T cell, and macrophage signaling. Expression of a number of noncoding RNAs were also altered following injury with microRNAs 143/145 being dramatically downregulated and microRNAs 1949 and 142 upregulated. Several long noncoding RNAs showed altered expression that mirrored the expression of their nearest coding genes. These data demonstrate that following carotid artery ligation an inflammatory cascade is initiated that is associated with the downregulation of coding and noncoding RNAs that are normally required to maintain smooth muscle cells in a differentiated state.

Abstract 307: Deficiency of Lim-only Protein Fhl2 Accelerates Neointima Formation After Carotid Artery Ligation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kondababu Kurakula ◽  
Vivian de Waard ◽  
Claudia M van Tiel ◽  
Carlie J de Vries
Keyword(s):  
Carotid Artery ◽  
Vascular Injury ◽  
Regulatory Function ◽  
Dependent Manner ◽  
Neointima Formation ◽  
Wild Type ◽  
Lesion Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Enhanced Expression

Rationale The LIM-only protein FHL2, also known as DRAL or SLIM3, has a regulatory function in many physiological processes and is expressed in the vessel wall in smooth muscle cells (SMCs) and endothelial cells, but not in macrophages. FHL2 regulates SMC phenotype, but its function in vascular injury is unknown. Objective To assess the role of FHL2 in SMC-rich lesion formation after vascular injury and to elucidate the underlying mechanism. Methods & Results Cultured aortic SMCs from FHL2-KO mice showed increased migration and increased proliferation through enhanced phosphorylation of extracellular-regulated kinase-1/2 (ERK1/2) and induction of CyclinD1 expression. In agreement with this, overexpression of FHL2 in SMCs reduced CyclinD1 expression. In addition, FHL2-KO SMCs showed enhanced expression of pro-inflammatory cytokines in a NFkB dependent manner. Consistent with these findings, NFkB activity is higher in FHL2-KO SMCs. In response to carotid artery ligation FHL2-deficient (FHL2-KO) mice developed accelerated lesion formation compared with wild-type (WT)-mice. Furthermore, FHL2-KO mice displayed high number of macrophages in lesions and enhanced expression of RANTES and stromal derived factor-1α (SDF-1α) in ligated carotid arteries. SDF-1α expression was also increased in plasma of FHL2-KO mice. Finally, FHL2-KO mice showed enhanced Ki67 expression in lesions compared with wild-type (WT)-mice. Conclusion FHL2 deficiency in mice results in an exacerbated neointima formation by enhanced proliferation and migration of SMCs, possibly regulated via ERK1/2 and NFkB pathway.

scholarly journals Protease nexin-1 deficiency increases mouse hindlimb neovascularisation following ischemia and accelerates femoral artery perfusion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Selbonne ◽  
Celina Madjene ◽  
Benjamin Salmon ◽  
Yacine Boulaftali ◽  
Marie-Christine Bouton ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Capillary Density ◽  
Leukocyte Recruitment ◽  
Lower Limbs ◽  
Artery Ligation ◽  
Angiogenic Balance ◽  
Important Player ◽  
Protease Nexin ◽  
Artery Perfusion

AbstractWe previously identified the inhibitory serpin protease nexin-1 (PN-1) as an important player of the angiogenic balance with anti-angiogenic activity in physiological conditions. In the present study, we aimed to determine the role of PN-1 on pathological angiogenesis and particularly in response to ischemia, in the mouse model induced by femoral artery ligation. In wild-type (WT) muscle, we observed an upregulation of PN-1 mRNA and protein after ischemia. Angiography analysis showed that femoral artery perfusion was more rapidly restored in PN-1−/− mice than in WT mice. Moreover, immunohistochemistry showed that capillary density increased following ischemia to a greater extent in PN-1−/− than in WT muscles. Moreover, leukocyte recruitment and IL-6 and MCP-1 levels were also increased in PN-1−/− mice compared to WT after ischemia. This increase was accompanied by a higher overexpression of the growth factor midkine, known to promote leukocyte trafficking and to modulate expression of proinflammatory cytokines. Our results thus suggest that the higher expression of midkine observed in PN-1- deficient mice can increase leukocyte recruitment in response to higher levels of MCP-1, finally driving neoangiogenesis. Thus, PN-1 can limit neovascularisation in pathological conditions, including post-ischemic reperfusion of the lower limbs.

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