link1: Surgery. 1996 May;119(5):494-7.Links
Increased mast cell infiltration in varicose veins of the lower limbs: a possible role in the development of varices.Yamada T, Tomita S, Mori M, Sasatomi E, Suenaga E, Itoh T.
Department of Emergency Medicine, Saga Medical School, Japan.
BACKGROUND. This study shows increased infiltration of mast cells in the walls of varicose veins in the lower limbs as an explanation of the pathogenesis of varix formation. METHODS. Great saphenous veins exhibiting varicosity were histologically examined after vein stripping surgery, and the numbers of mast cells in the varicose lesions were estimated in 20 high-power fields (x400). Normal-looking regions of the veins were referred to as controls, and normal saphenous veins were prepared during coronary artery bypass grafting and designated baseline controls. RESULTS. The varicose lesions showed a greater extent of mast cell infiltration (15.0 +/- 8.4 cells; mean +/- standard deviation), whereas control veins (5.9 +/- 4.0) and baseline control veins (4.4 +/-2.9) had a smaller number of mast cells. CONCLUSIONS. The study suggests that increased mast cell infiltration contributes to the development of varicose veins.
PMID: 8619202 [PubMed - indexed for MEDLINE]
ink1: Int Angiol. 2003 Mar;22(1):43-9.Links
Increased mast cell infiltration in familial varicose veins: pathogenetic implications?Kakkos SK, Zolota VG, Peristeropoulou P, Apostolopoulou A, Geroukalos G, Tsolakis IA.
University of Patras Medical School, Patras, Greece.
AIM: Increased infiltration of activated mast cells has been recently implicated in the pathophysiology of varicose veins. The aim of the present study was to investigate a possible association between mast cell infiltration of primary varicose veins and clinical features, which could clarify further varicose vein pathophysiology. METHODS: Seventeen patients, operated on for primary varicose veins and greater saphenous vein incompetence, participated in the study. Mast cells, distributed within the adventitia of grossly abnormal segments of the greater saphenous vein and calf varicosities removed during surgery, were identified and measured in stained tissue sections. The mast cell count, expressed as mast cells per 10 high-power fields, was subsequently associated with clinical features, including age, gender, body mass index, familial varicose veins, duration of varicose vein disease and relation to previous pregnancies, leg symptoms and findings on physical examination, clinical class and score of chronic venous insufficiency (CEAP classification). RESULTS: Patients with family history of varicose veins (n=7) had a significantly increased mast cell infiltration (median, interquartile range) of the abnormal venous segments (16, 8.4) in comparison with those (n=10) without such a history (9.2, 7.3), p=0.005. Mast cell infiltration had a significant inverse association with age (r= -0.49, p=0.046), but not with the remaining clinical features. CONCLUSION: Our findings support the hypothesis that the increased mast cell infiltration in varicose veins is not a consequence of venous hypertension. Furthermore, the increased mast cell infiltration in familial varicose veins implies a rather primary role and therefore the presence of a distinct pathophysiology. Further investigation testing the activity of mast cells in cases of family history might reveal another step in the pathogenic mechanism of varicose veins, leading to a more rational treatment.
PMID: 12771855 [PubMed - indexed for MEDLINE]
and back to Bax (upregulated by broccoli sprouts)
link1: Eur J Vasc Endovasc Surg. 2008 Feb;35(2):224-9. Epub 2007 Oct 23. Links
Association of primary varicose veins with dysregulated vein wall apoptosis.Ducasse E, Giannakakis K, Speziale F, Midy D, Sbarigia E, Baste JC, Faraggiana T.
Unit of Vascular Surgery, Hospital Tripode-Pellegrin, Université de Bordeaux 2, CHU de Bordeaux, Bordeaux, France. firstname.lastname@example.org
BACKGROUND: Disordered programmed cell death may play a role in the development of superficial venous incompetence. We have determined the number of cells in apoptosis, and the mediators regulating the intrinsic and extrinsic pathways in specimens of varicose vein. METHODS: Venous segments were obtained from 46 patients undergoing surgical treatment for primary varicose veins. Controls samples were obtained from 20 patients undergoing distal arterial bypass grafting surgery. Segments of the distal and proximal saphenous trunk as well as tributaries were studied. Cell apoptoses and mediators of the mitochondrial and trans membrane pathway were evaluated with peroxidase in situ apoptosis detection, Bax and Fas detection, caspase-9 and 8 detection in the medial layer. RESULTS: Disorganised histological architecture was observed in varicose veins. Primary varicose veins also contained fewer peroxidase in situ-positive cells than control veins (2.6% S.D. 0.2% versus 12% S.D. 0.93%, P=.0001, Mann-Whitney u test), fewer Bax positive cells (2.1.% S.D. 0.3% versus 13% S.D. 0.9%, P=.0001) and fewer Caspase 9 positive cells (3.2% S.D. 1% versus 12% S.D. 1.3%, P=.0001). Similar findings were observed in saphenous trunk, main tributaries and accessory veins. In patients with recurrent varicose veins in whom the saphenous trunk had been preserved showed similar findings to primary varicose veins. Residual varicose veins contained fewer peroxidase in situ-positive cells than healthy veins (3.2% S.D. 0.6% versus 11% S.D. 2%, P=.0001), fewer Bax positive cells (2.2% S.D. 0.3% versus 12% S.D. 0.7%, P=.0001) and fewer Caspase 9 positive cells (2.6% S.D. 0.6% versus 12% S.D. 1%, P=.0001). Immunohistochemical detection for Fas and caspase 8 remained equal was the same in the varicose vein and control groups. CONCLUSION: Apoptosis is down regulated in the medial layer of varicose veins. This dysregulation is attributable to a disorder of the intrinsic pathway and involves the great saphenous vein trunk, major tributaries and accessory veins. This process may be among the causes of primary varicose veins.
PMID: 17936650 [PubMed - indexed for MEDLINE]
link1: Histol Histopathol. 2000 Jul;15(3):745-52.Links
Evaluation of the smooth muscle cell component and apoptosis in the varicose vein wall.Buján J, Jiménez-Cossio JA, Jurado F, Gimeno MJ, Pascual G, García-Honduvilla N, Dominguez B, Bellón JM.
Department of Morphological Sciences and Surgery, Faculty of Medicine, University of Alcalá, Madrid, Spain. email@example.com
This study was designed to evaluate the role of the smooth muscle cell and the apoptosis in the pathogenesis of the varicose vein. Segments of saphenous vein were obtained from healthy subjects and from those with varicose veins. The vein specimens were subdivided according to subject age (younger or older than 50 years) and according to the varicose vein source (distal or proximal). Morphological, ultrastructural, cell proliferation (anti-PCNA method) and cell death (TUNEL method) analysis were performed. The walls of healthy, control vein specimens acquired a more collagenous and papillomatous appearance with age. A slight increase in the number of TUNEL-positive cells was also observed in specimens from older subjects. The proportion of apoptotic cells was much greater in the varicose veins than in control specimens. Most cellular alterations were seen in proximal varicose segments obtained from young subjects. These specimens showed hypertrophic areas with a high degree of cellularity (both in the media and in the thickened intima). The highest proportion of apoptotic cells and collagenisation were also observed in these areas. The enhanced number of apoptotic cells in varicose veins observed mainly in proximal/young vein specimens could be responsible, at least in part, for the acceleration of the final fibrosclerotic process characteristic of the varicose vein wall.
PMID: 10963119 [PubMed - indexed for MEDLINE]
but then again I think broccoli sprouts must be good since broccoli sprouts upregulate Bax (see Natural section in forum)
linl1: J Vasc Surg. 2001 May;33(5):1080-6. Links
Expression of molecular mediators of apoptosis and their role in the pathogenesis of lower-extremity varicose veins.Ascher E, Jacob T, Hingorani A, Tsemekhin B, Gunduz Y.
Division of Vascular Surgery, Maimonides Medical Center, Brooklyn, NY, USA.
PURPOSE: In an earlier study, we observed a significant decrease in apoptosis in varicose veins, as compared with healthy veins, indicating that deregulated apoptosis plays a role in the pathogenesis of varicosities. In addition, significant differences were noted in the expression and subcellular localization of the cell cycle regulatory protein, cyclin D1 in varix tissues, as compared with controls. Because cell cycle checkpoint controls are linked to the signaling and execution of apoptotic cascades, we examined the expression of bcl-2 family members bax and bcl-x, known molecular mediators of apoptosis, and that of poly (ADP-ribose) polymerase (PARP), a downstream substrate of DNA cleavage. METHODS: Twenty varicose vein specimens were retrieved from 20 patients (10 men, 10 women; mean age, 53.6 +/- 4.7 years) undergoing lower-extremity varicose vein excision. Healthy greater saphenous vein segments (n = 27) were obtained from 27 patients (14 men, 13 women; mean age, 59.5 +/- 2.4 years) undergoing infrainguinal arterial bypass grafting surgery. All tissues were distal portions. As per CEAP classification for chronic lower-extremity venous disease, most of the patients were in class 2 for clinical signs (n = 11); some patients were in class 3 (n = 4) or class 4 (n = 4), and only one patient was in class 5. Five 5-microm thick sections from formalin-fixed, paraffin-embedded specimens were used as a means of immunohistochemically localizing the expression of bax, bcl-x, and PARP, and 10 random high-power fields per section were evaluated by two independent reviewers blinded to the clinical findings. Statistical analyses were conducted by means of chi(2), analysis of variance, Student and Fisher exact t tests with StatView software. RESULTS: Immunoreactivity to pro-apoptotic bax was significantly higher in the normal veins (P <.001). Cytoplasmic expression of bcl-x was prominent in the cells of the vasa vasorum in both varicose and healthy veins. PARP expression was diminished in the varicose vein group, with 2.8 +/- 0.7 (P =.01) and 1.4 +/- 0.5 (P =.05) cells per high-power field in the intima and media, respectively. Neither bax nor PARP was noted in the adventitia of varicose veins, although their expression was detected in this layer of the control group (P <.001). CONCLUSION: The entry of smooth muscle cells into the apoptotic pathway may be regulated by the induction of bax in this model, because there is significant presence of this pro-apoptotic protein in healthy veins. Both bax and PARP are downregulated in varicose veins, as compared with healthy veins, and this may play a significant role in the pathogenesis of varicose veins.
PMID: 11331852 [PubMed - indexed for MEDLINE]
maybe calcium dobesilate for apoptosis regulation:
link1: Vasa. 2008 Aug;37(3):233-40.Links
Effects of calcium dobesilate and diosmin-hesperidin on apoptosis of venous wall in primary varicose veins.Iriz E, Vural C, Ereren E, Poyraz A, Erer D, Oktar L, Gokgoz L, Halit V, Soncul H.
Gazi University, School of Medicine, Department of Cardiovascular Surgery, Ankara, Turkey. firstname.lastname@example.org
BACKGROUND: Evaluation of the therapeutic effects of calcium dobesilate and diosmin-hesperidin through regulation of apoptosis. PATIENTS AND METHODS: 56 Patients were divided into four groups; Group 1 consisted of patients (n = 18) with the recent diagnosis of primary varicose disorder who have never used medications, Group 2 consisted of patients (n = 14) who have used diosmin-hesperidin for at least six weeks prior to the operation, Group 3 consisted of patients (n = 14) who have used calcium dobesilate for at least six weeks prior to the operation and finally Group 4 (Control group) consisted of normal saphenous vein biopsies (n = 10). All biopsies were stained with Hematoxylin and Eosin. Tissue samples from 56 patients were immunohistochemically stained with antibodies of anti-bcl-2, anti-bax and anti-p53. Apoptosis was evaluated by TUNEL method. RESULTS: There were no statistically significant differences among the groups in respect to gender distribution and smoking status. Immunohistochemical evaluation of apoptosis related proteins revealed a statistically significant difference between Group 4 and the other groups with respect to the apoptag staining on venous wall (p = 0.026). There were significant differences in the presence of bcl-2 protein expression between groups 4 and Group 1 (p = 0.0002) and between Group 1 and Group 3 (p = 0.023). CONCLUSIONS: Our study highlights the significance of apoptosis in varicose disorders and suggests that calcium dobesilate, which is used in the treatment of varicose veins, could be of benefit by regulating apoptosis.
PMID: 18690590 [PubMed - indexed for MEDLINE]
transforming growth factor beta 1 seems dysregulated in varicose veins:
link1: J Vasc Res. 2007;44(3):192-201. Epub 2007 Feb 27. Links
TGF-beta1 upregulation in the aging varicose vein.Pascual G, Mendieta C, García-Honduvilla N, Corrales C, Bellón JM, Buján J.
Department of Medical Specialities, Faculty of Medicine, University of Alcala, Alcalá de Henares, Madrid, Spain.
BACKGROUND: Although the etiology of venous insufficiency is not well understood, immune response and aging are beginning to emerge as contributing factors. Factors involved in tissue remodeling such as TGF-beta(1) also seem to play an important role in extracellular matrix production. The aim of this study was to explore the relationship between chronic venous insufficiency and TGF-beta(1) examining the latent/mature form of TGF-beta(1) and the presence of mast cells. Effects of age were also evaluated. METHODS: Saphenous veins were obtained from patients subjected to aortocoronary bypass (controls) and undergoing varicose vein surgery. These were immunolabeled using anti-LAP TGF-beta(1)/anti-TGF-beta(1) antibodies and subjected to Western blot. Mast cell population was identified by metachromatic staining. RESULTS: Latent TGF-beta(1) was significantly reduced in varicose veins from older subjects. In contrast, smooth muscle cells obtained from the varicosities showed intense levels. Mature TGF-beta(1) significantly differed between healthy and varicose veins. No mature TGF-beta(1) was detected in the cell cultures. Mast cell number and degranulation were increased with aging and varicose disease, colocalizing with the mature form of TGF-beta(1). CONCLUSION: Aging and varicose pathology induce dysregulation of TGF-beta(1) that could play an important role in the fibrous process, representing the final stages of venous insufficiency.
PMID: 17337905 [PubMed - indexed for MEDLINE]
seems as though TGF-beta1 is in the areas of stenoses:
[color]blue]link[/color]1: J Vasc Surg. 2005 Mar;41(3):523-30. Links
Overexpression of transforming growth factor-beta1 correlates with increased synthesis of nitric oxide synthase in varicose veins.Jacob T, Hingorani A, Ascher E.
Division of Vascular Surgery, Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USA.
INTRODUCTION: Transforming growth factor-beta 1 (TGF-beta 1 ) is known to maintain a balance between apoptosis and cellular dysfunction and therefore may have a pivotal role in vessel remodeling during pathogenesis of vascular disorders. We previously demonstrated that inducible nitric oxide synthase (iNOS) mediates signal transduction in vascular wall during the development of varicose veins. Currently, we investigated the expression and correlation of TGF-beta 1 , iNOS, monocyte/macrophage infiltration, and loss of vascular smooth muscle cells (VSMCs), in a series of normal and varicose vein specimens. METHODS: Twenty varicose vein specimens were retrieved from 20 patients undergoing lower-extremity varicose vein excision, and 27 normal greater saphenous vein segments (controls) were obtained from 27 patients undergoing infrainguinal arterial bypass surgery. Principal risk factors (diabetes mellitus, hypertension, tobacco abuse) were also compared. Varicose vein segments were separated into tortuous and nontortuous regions based on their macroscopic and microscopic morphology. VSMC actin, CD68 + monocytes/macrophages, iNOS, and TGF-beta 1 , were examined by immunohistochemistry, immunoblotting, and real-time reverse transcriptase polymerase chain reaction. RESULTS: According to the CEAP classification for chronic lower extremity venous disease, most of the patients were in class 2 for clinical signs of the disease (n = 11). Mean ages were 53.6 +/- 4.7 years for the varicose vein group and 56.5 +/- 4.4 years for the controls. The gender distribution was same in both groups. Immunoreactivity to TGF-beta 1 and iNOS was significantly different in the tortuous regions of the varicose veins compared with nontortuous regions (P < .01). Not only was a significantly higher expression of iNOS noted in the varicose vein group (P < .001), but a differential expression of iNOS was also observed in the tortuous and nontortuous portions of the varicose veins. Significant overexpression of TGF-beta 1 (P < .01) that correlated with overproduction of iNOS and with increased presence of CD68 + monocytes/macrophages was observed in the varicose vein walls compared with normal veins. CONCLUSIONS: This is the first evidence of TGF-beta 1 , as well as iNOS, being differentially upregulated in nontortuous and tortuous segments of varicose veins. The increased expression of TGF-beta 1 and presence of macrophages, correlating with overproduction of iNOS, may be associated with varicosity development and deserves further study. CLINICAL RELEVANCE: The pathogenesis of varicose veins, the most common manifestation of chronic venous disease, is debatable. Elucidation of mechanisms involved in the disease process is the first step to improved therapeutic modulations. Towards this goal, the relationship between NO production and TGF-beta 1 in the molecular pathophysiology of chronic venous disease was investigated. The data identify for the first time, an important role for TGF-b1-iNOS-monocyte/macrophage signaling in the etiology of varicosities. Furthermore, we determine if there are any significant differences within the varicose vein group itself based on regional differences, by classifying the varicose tissues into tortuous and non-tortuous segments.
PMID: 15838489 [PubMed - indexed for MEDLINE]
seems like TGF-beta1 is a gene commonly expressed in MS. Not sure if the TGF-beta1 above is the same as the gene though...but seems possible...
[colour=blue]link[/color]1: BMC Med Genet. 2008 Mar 19;9:17. Links
Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.Arthur AT, Armati PJ, Bye C; Southern MS Genetics Consortium, Heard RN, Stewart GJ, Pollard JD, Booth DR.
Department of Medicine and the Nerve Research Foundation, the University of Sydney, Sydney, Australia. email@example.com
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. METHODS: In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. RESULTS: Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. CONCLUSION: The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
PMID: 18366677 [PubMed - indexed for MEDLINE]
downregulation of endothelin receptors in varicose tissue:
link1: Zhonghua Wai Ke Za Zhi. 2008 Sep 1;46(17):1325-8.Links
[The relationship between endothelin receptors and chronic venous insufficiency of lower extremities][Article in Chinese]
Yang L, Qi GY, Cao YX, Liu J, Zhao M.
Department of General Surgery, the First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China. firstname.lastname@example.org
OBJECTIVE: To investigate the effect of endothelin receptors in chronic venous insufficiency (CVI) in lower extremities. METHODS: Ten cases of varicose veins from CVI patients (as case group) and ten cases of non-varicose veins (as control group) were investigated in this study. The two groups were divided into two groups respectively: endothelium-intact group and de-endothelium groups. The vasoconstriction mediated by endothelin A (ETA) and endothelin B (ETB) receptors was recorded with myography. The distribution of ETA and ETB receptors was detected by immunohistochemistry method. RESULTS: Endothelin-1 (ET-1) and sarafotoxin 6c (S6c) induced concentration-dependent contraction in the veins. In endothelium-intact veins, the E(max) and pD(2) of contraction curve induced by ET-1 were 132.30% +/- 43.42% and 6.03 +/- 0.35, respectively in control group;and were 19.24% +/- 12.94% and 6.78 +/- 0.46, respectively in case group. The E(max) and pD(2) in case group were much lower than in control group (P < 0.05). The E(max) and pD(2) induced by S6c were 30.10% +/- 12.90% and 6.54 +/- 0.36, respectively in control group, and were 9.61% +/- 1.32% and 6.75 +/- 0.29, respectively in case group; The E(max) in case group was lower than in control group (P < 0.05). In de-endothelium veins, E(max) and pD(2) of S6c were 146.18% +/- 32.33% and 6.50 +/- 0.17 in control group, and 32.93% +/- 3.00% and 6.69 +/- 0.39 in case group; The E(max) in case group was significantly lower than in control group (P < 0.05). ETA receptors was located in endothelium mainly, and ETB receptors in smooth muscle cells mainly. The sites of both ETA and ETB receptors were decreased in case group obviously. CONCLUSIONS: The contraction mediated by ETA receptor and ETB receptor was decreased with a decrease of ETA receptor and ETB receptor sites in varicose veins of CVI. The contraction insufficiency and down-expression of ETA receptor and ETB receptor are correlated with CVI.
PMID: 19094564 [PubMed - in process]
link1: Agents Actions Suppl. 1995;45:237-53.Links
Endothelin and endothelin antagonists: pharmacology and clinical implications.Lüscher TF, Wenzel RR.
University Hospital, Inselspital, Bern/Switzerland.
Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.
PMID: 7717186 [PubMed - indexed for