scholarly journals Pharmacological blockade of histone methyltransferase SETD7 restores angiogenic response in experimental diabetes

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Mohammed ◽  
S C Costantino ◽  
A A Akhmedov ◽  
G K Karsay ◽  
S A Ambrosini ◽  
...  
Keyword(s):  
Blood Flow ◽  
Blood Vessel ◽  
Experimental Diabetes ◽  
Tube Formation ◽  
Diabetic Patients ◽  
Rna Seq ◽  
Angiogenic Response ◽  
Histone 3 ◽  
Vessel Growth ◽  
Pharmacological Blockade

Abstract Background Peripheral artery disease (PAD) is highly prevalent in patients with diabetes and associates with a high rate of limb amputation and poor prognosis. Surgical and catheter-based revascularization have failed to improve outcome in diabetic patients with PAD. Hence, a need exists to develop new treatment strategies able to promote blood vessel growth in the ischemic limb of diabetic patients. Mono-methylation of histone 3 at lysine 4 (H3K4me1) - a specific epigenetic signature induced by the methyltransferase SETD7 - favours a chromatin active and open state thus enabling the gene transcription. Purpose To investigate whether SETD7-dependent epigenetic changes modulate post-ischemic vascularization in experimental diabetes. Methodology Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 20 mM) concentrations for 48 hours. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). In vitro angiogenic assays like migration assay & tube formation assay were performed. Pharmacological blockade of SETD7 was achieved by using the highly selective inhibitor called (R)-PFI-2. T1D mice (streptozotocin-induced diabetes) was orally treated with (R)-PFI-2 and with vehicle for 21 days and followed by induction of hindlimb ischemia. Blood flow recovery was analyzed at 30 minutes, 7 and 14 days by laser doppler imaging. Gastrocnemius muscle samples from patients with and without T2D were employed to translate our experimental findings. Results RNA-seq in HG-treated HAECs revealed a profound upregulation of the methyltransferase SETD7, an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). SETD7 upregulation in HG-treated HAECs was associated with an increase of H3K4-mono-methylation levels as well as with impaired endothelial cell migration and tube formation. Of interest, both gene silencing (SETD7-siRNA) and pharmacological blockade of SETD7 by (R)-PFI-2 rescued hyperglycemia-induced impairment of angiogenic properties in HAECs. RNA-seq in HG-treated HAECs with and without SETD7 depletion unveiled an array of differentially expressed genes, which were mainly involved in blood vessel growth and angiogenic response. Among dysregulated genes, Chromatin immunoprecipitation (ChIP) assays showed that SETD7 specifically mono-methylates H3K4m1 in proximity of Semaphorin-3G (SEMA3G) promoter, thus regulating its expression. Treatment of T1D mice with (R)-PFI-2 improved blood flow reperfusion at 14 days as compared to vehicle-treated animals. Finally, SETD7/SEMA3G axis was upregulated in muscle specimens from T2D patients. Conclusion Targeting SETD7 represents a novel epigenetic-based therapy to boost neovascularization in diabetic patients with PAD. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

P736Histone marks induced by the methyltransferase SETD7 modulate angiogenic response in diabetes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S A Mohammed ◽  
S Costantino ◽  
A Akhmedov ◽  
S Ambrosini ◽  
G Karsay ◽  
...  
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
Tube Formation ◽  
Endothelial Cell Migration ◽  
Rna Seq ◽  
Hindlimb Ischemia ◽  
Angiogenic Response ◽  
Pharmacological Blockade ◽  
Type 2 Diabetic

Abstract Introduction Despite advances in revascularization strategies, type 2 diabetic (T2D) patients with peripheral artery disease (PAD) continue to have a high risk of limb amputation. Hence, strategies that promote vascularization can be considered as a novel therapeutic option in T2D patients with PAD. Epigenetic modifications of histones and DNA have emerged as key modulators of gene expression. Mono-methylation of histone 3 at lysine 4 (H3K4m1) – a specific epigenetic signature induced by the methyltransferase SETD7 – favours a chromatin conformation enabling the transcription of genes involved in inflammation and oxidative stress. Purpose To investigate whether SETD7 modulates angiogenesis in experimental diabetes. Methods Human aortic endothelial cells (HAECs) were cultured in growth factor-free medium and exposed either to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48 hours. SETD7 protein and H3K4me1 levels were investigated by Western blot and chromatin immunoprecipitation (ChIP). Knockdown of SETD7 was achieved by small interfering RNA (siRNA). Pharmacological blockade of SETD7 was performed by using the highly selective inhibitor (R)-PFI-2, while its inactive enantiomer, (S)-PFI-2, was used as a control. Scratch and tube formation assays were performed to investigate the impact of SETD7 on angiogenic properties of HAECs. RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) were employed to unveil putative genes regulated by SETD7 in HG-treated HAECs. SETD7 expression was also investigated in muscular specimens isolated from type 2 diabetic (db/db) mice and non-diabetic mice undergoing hindlimb ischemia for 21 days. Results HG exposure in HAECs led to a time-dependent increase of both SETD7 gene and protein expression, as compared to NG. SETD7 upregulation in HG-treated HAECs was associated with an increase of H3K4me1 levels as well as with impaired endothelial cell migration and tube formation. Of interest, both gene silencing and pharmacological blockade of SETD7 rescued hyperglycemia-induced impairment of angiogenic properties in HAECs. RNA-seq in HG-treated HAECs with and without SETD7 depletion unveiled an array of differentially expressed genes, which were mainly involved in blood vessel growth and angiogenic response, as assessed by IPA analysis. Among dysregulated genes, ChIP assays showed that SETD7-dependent chromatin changes enabled the transcription of Semaphorin 3G (SEMA-3G), a negative regulator of endothelial cell migration. Indeed, gene silencing of SETD7 blunted SEMA-3G expression in HAECs exposed to HG. Consistent with our in vitro observations, SETD7 was upregulated in adductor muscle specimens from db/db mice undergoing hindlimb ischemia as compared to non-diabetic animals. Conclusions Pharmacological blockade of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to boost post-ischemic vascularization in T2D patients with PAD.

scholarly journals The BET protein inhibitor apabetalone (RVX-208) restores angiogenic response in type 1 and type 2 diabetes by transcriptional regulation of thrombospondin-1

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Mohammed ◽  
M A Mattia ◽  
G K Gergely ◽  
G S Gaia ◽  
S A Ambrosini ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Flow ◽  
Gastrocnemius Muscle ◽  
Tube Formation ◽  
Public Institution ◽  
Diabetic Patients ◽  
Angiogenic Response ◽  
Bet Protein ◽  
The Impact

Abstract Background Peripheral artery disease (PAD) is highly prevalent in people with type 2 diabetes and associates with chronic limb ischemia and poor prognosis. Understanding the mechanisms of impaired blood vessel growth in diabetic patients is of paramount importance to develop new angiogenic therapies in this setting. Dysregulation of epigenetic mechanisms of gene transcription in vascular cells contributes to cardiovascular disease development but is currently not targeted by therapies. Apabetalone (RVX-208) – an FDA approved small molecule inhibitor of the epigenetic readers bromodomain and extra-terminal (BET) proteins – has recently shown to modulate transcriptional programs implicated in vascular inflammation and atherosclerosis. Purpose To investigate RVX-208 effects in modulating angiogenic response and post-ischemic vascularization in diabetes. Methods Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 20 mM) for 48 hours in presence of RVX-208 (20μM) or vehicle (DMSO). Scratch and tube formation assays were performed to investigate the impact of RVX-208 on angiogenic properties of HAECs. T1D mice (streptozotocin-induced diabetes) and T2D mice (Lepdb/db) were orally treated with apabetalone or vehicle for 5 days. Hindlimb ischemia was induced in T1D mice & blood flow recovery analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Sprouting and matrigel plug assays were performed in Lepdb/db mice. Gastrocnemius muscle samples from patients with and without T2D were employed to translate our experimental findings. Results HG impaired HAECs migration and tube formation as compared to NG, whereas treatment with RVX-208 rescued HG-induced impairment of angiogenic properties. Real time PCR arrays in HG-treated HAECs showed that RVX-208 treatment prevents the dysregulation of genes implicated in endothelial migration, sprouting and inflammation, namely the anti-angiogenic molecule thrombospondin (THBS1), VEGF-A, IL-1β, IL-6, VCAM-1, and CXCL1. Of interest, both gene silencing of BET protein (BRD4) or its pharmacological inhibition by RVX-208 reduced THBS1 expression while restoring VEGFA levels in HG-treated HAECs. ChIP assays showed the enrichment of both BRD4 and the active chromatin mark H3K27Ac on THBS1 promoter. Mechanistic experiments uncovered the inhibitory role of THBS1 on VEGFA signalling, as also confirmed by STRING analysis. Treatment of T1D mice with RVX-208 improved blood flow reperfusion and vascular density at 14 days as compared to vehicle-treated animals. Moreover, RVX-208 restored endothelial sprouting in T2D-Lepdb/db mice. Of clinical relevance, THBS1 was upregulated while VEGFA expression was reduced in gastrocnemius muscle specimens from T2D patients with PAD as compared to non-diabetic controls. Conclusion In vivo targeting of BET-proteins by RVX-208 may represents a novel therapeutic approach to boost post-ischemic neovascularization in diabetes. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

A chromatin signature by the methyltransferase SETD7 regulates semaphorin-3G transcription and angiogenic response in diabetes: insights for personalized epigenetic therapies

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.A Mohammed ◽  
S Costantino ◽  
A Akhmedov ◽  
G Karsai ◽  
S Ambrosini ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gastrocnemius Muscle ◽  
Tube Formation ◽  
Public Institution ◽  
Epigenetic Therapy ◽  
Great Promise ◽  
Funding Source ◽  
Rna Seq ◽  
Angiogenic Response ◽  
Pharmacological Inhibition

Abstract Background Despite advances in revascularization strategies, type 2 diabetic (T2D) patients with peripheral artery disease (PAD) continue to have a high risk of limb amputation. Modulation of blood vessel growth holds great promise for the treatment of PAD patients. Epigenetic modifications, namely histone post-translational modifications, have shown to regulate transcriptional programs implicated in the pathogenesis of cardiovascular disease. Aim To investigate the role of chromatin changes in regulating post-ischemic vascularization in experimental diabetes as well as in patients with T2D. Methods Experiments were performed in primary human aortic endothelial cells (HAECs), double-mutant leptin deficient mice (Lepdb/db) carrying a genetic deletion of the methyltransferase SETD7 (Setd7−/−Lepdb/db) as well as in gastrocnemius muscle samples from T2D patients with PAD and age-matched non-diabetic controls. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). Pharmacological blockade of SETD7 was performed by using the selective inhibitor (R)-PFI-2. Scratch and tube formation assays were performed to investigate the impact of SETD7 on angiogenic response. Results RNA-seq in high glucose-treated HAECs revealed a profound upregulation of the methyltransferase SETD7 (fold change 2.8, p<0.001), an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and Chromatin Immunoprecipitation (ChIP) assays showed that SETD7-dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G). Increased SEMA-3G transcript was associated with enhanced secretion from HAECs. Co-immunofluorescence experiments showed that SEMA-3G blunts the angiogenic response by competing with VEGF receptors VEGFR/Neuropillin2. Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. SETD7 and SEMA-3G were significantly upregulated in endothelial cells from Lepdb/db mice, whereas SEMA-3G transcription was blunted in Setd7−/−Lepdb/db animals. Consistently, endothelial sprouting was defective in aortas from Lepdb/db as compared to WT mice, whereas Setd7−/−Lepdb/db mice displayed a preserved angiogenic response. Of clinical relevance, SETD7/SEMA-3G axis was upregulated in gastrocnemius muscle specimens from T2D patients with PAD as compared with non-diabetic controls. Conclusion In HAECs, genetically modified mice and T2D patients we show that SETD7-dependent chromatin changes regulate SEMA-3G transcription and angiogenic response. Pharmacological inhibition of SETD7 may represent a novel epigenetic therapy to boost neovascularization in T2D patients with PAD. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Zurich/Universitätsspital Zürich

scholarly journals The influence of high glucose concentration on the ability of mesenchymal stromal cells to stimulate blood vessel growth

2011 ◽  
Vol 14 (2) ◽  
pp. 32-35 ◽  
Author(s):  
Zhanna Alekseevna Akopyan ◽  
Georgy Vladimirovich Sharonov ◽  
Tatiana Nikolaevna Kochegura ◽  
Natalya Fedorovna Il'yashenko ◽  
Igor Eduardovich Belyanko ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Blood Vessel ◽  
High Glucose ◽  
Glucose Concentration ◽  
Functional Activity ◽  
Human Adipose Tissue ◽  
Diabetic Patients ◽  
High Glucose Concentration ◽  
Vessel Growth ◽  
Negative Effect

Adipose issue is a source of mesenchymal stem cells (MSC) that can be used to stimulate blood vessel growth in ischemic tissues. Various metabolicdisorders including hypeglycemia may have negative effect on therapeutic properties of these cells. Aim. To study the influence of high glucose concentration on functional activity in human adipose tissue. Materials and methods. Flow cytometry and real time PCR were used to study functional activity of cultured MSC from human adipose issue at highglucose concentration. Results. Prolonged (10-12 days) incubation at a high glucose concentration (25 mM) suppressed the ability of MSC to stimulate angiogenesis. Also,glucose modified expression of genes activating and inhibiting angiogenesis but had no effect on MSC proliferation and apoptosis. Conclusion. High glucose concentration suppresses angiogenic activity of MSC in adipose tissue; it may account for incomplete restoration of bloodflow in diabetic patients.

scholarly journals Endothelial overexpression of metallothionein prevents diabetes mellitus-induced impairment in ischemia angiogenesis via preservation of HIF-1α/SDF-1/VEGF signaling in endothelial progenitor cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Kai Wang ◽  
Xiaozhen Dai ◽  
Junhong He ◽  
Xiaoqing Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Flow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Mononuclear Cells ◽  
Tube Formation ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Endothelial Progenitor ◽  
Vegf Signaling

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high fat diet and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in <i>db/db</i> mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from diabetic patients exhibited decreased MT expression, increased cell apoptosis and impaired tube formation; while cultured JTMT-EPCs had enhanced cell survival, migration, and tube formation in hypoxia/hyperglycemic conditions compared with WT-EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1) and vascular endothelial growth factor (VEGF) expression, and reduced oxidative stress in ischemic tissues. MT’s pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting MT’s anti-oxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC functions most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

Abstract 23: Exosome Inhibition Improved Blood Perfusion in Ischemic Hindlimb of db/db Diabetic Mice

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Zhongjian Cheng ◽  
Venkata Naga Srikanth Garikipati ◽  
Maria Cimini ◽  
Chunlin Wang ◽  
May Trungcao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Tube Formation ◽  
Tissue Loss ◽  
Diabetic Patients ◽  
Post Injury ◽  
Patients With Diabetes

Background: Critical limb ischemia (CLI), a life-threatening condition characterized by pain at rest and tissue loss with ulcer and gangrene, imposes a major public healthy burden, resulting in high mortality and disability. The occurrence of CLI in patients with diabetes mellitus is very frequent. However, the effective therapy for CLI in diabetic patients is absent. Recent studies demonstrated that exosome from diabetic animals/cells has detrimental effects on the post-injury cardiovascular repair. Here, we tested the hypotheses that exosome inhibition in vivo improves blood flow recovery and protects skeletal muscle in ischemic hindlimbs of diabetic db/db mice following surgical ischemia. Methods and Results: Exosomes were isolated from bone-marrow derived progenitor cells or plasma in non-diabetic db/+ and diabetic db/db mice by ultracentrifugation. Diabetic exosome (5 ug/ml) inhibited tube formation of human cardiac microvascular endothelial cells. Unilateral hindlimb ischemia surgery was conducted by ligation of left femoral artery in 12-week old, male db/+ and db/db mice. Exosome inhibitor GW4869 (2 μg/g body weight) was given by intraperitoneal injection every other day for 4 weeks starting from one week before the HLI surgery. HLI mice injected with vehicle served as controls. Mice were divided into four groups: 1) db/+ + vehicle; 2) db/db+ vehicle; 3) db/+ GW4869; 4) db/db + GW4869. GW4869 decreased necrosis and loss of toe/toenail, improved blood flow, enhanced capillary/arterial density, skeletal muscle architecture and cell survival in ischemic hindlimb of diabetic db/db mice 21 days post-ligation. Conclusions: Although preliminary, our experiments suggest that therapeutic targeting of dysfunctional exosome secretion could represent a new avenue for the prevention and treatment of ischemic injury in diabetic patients.

scholarly journals Endothelial overexpression of metallothionein prevents diabetes mellitus-induced impairment in ischemia angiogenesis via preservation of HIF-1α/SDF-1/VEGF signaling in endothelial progenitor cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Kai Wang ◽  
Xiaozhen Dai ◽  
Junhong He ◽  
Xiaoqing Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Flow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Mononuclear Cells ◽  
Tube Formation ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Endothelial Progenitor ◽  
Vegf Signaling

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high fat diet and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in <i>db/db</i> mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from diabetic patients exhibited decreased MT expression, increased cell apoptosis and impaired tube formation; while cultured JTMT-EPCs had enhanced cell survival, migration, and tube formation in hypoxia/hyperglycemic conditions compared with WT-EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1) and vascular endothelial growth factor (VEGF) expression, and reduced oxidative stress in ischemic tissues. MT’s pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting MT’s anti-oxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC functions most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

COMPARISON OF ANTIHYPERTENSIVE EFFECT OF MOXONIDINE VERSUS CLONIDINE IN RENAL FAILURE PATIENTS.

2018 ◽  
Vol 6 (9) ◽  
Author(s):  
DR.MATHEW GEORGE ◽  
DR.LINCY JOSEPH ◽  
MRS.DEEPTHI MATHEW ◽  
ALISHA MARIA SHAJI ◽  
BIJI JOSEPH ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Failure ◽  
Blood Flow ◽  
Blood Vessel ◽  
Blood Vessels ◽  
High Blood Pressure ◽  
Antihypertensive Effect ◽  
The Body ◽  
Ability To Work ◽  
Blood Flows

Blood pressure is the force of blood pushing against blood vessel walls as the heart pumps out blood, and high blood pressure, also called hypertension, is an increase in the amount of force that blood places on blood vessels as it moves through the body. Factors that can increase this force include higher blood volume due to extra fluid in the blood and blood vessels that are narrow, stiff, or clogged(1). High blood pressure can damage blood vessels in the kidneys, reducing their ability to work properly. When the force of blood flow is high, blood vessels stretch so blood flows more easily. Eventually, this stretching scars and weakens blood vessels throughout the body, including those in the kidneys.

Blood Vessel Density Measured Using Dynamic Optical Coherence Tomography is a Tool for Wound Healers

2021 ◽  
pp. 153473462110173
Author(s):  
Rajgopal Mani ◽  
Jon Holmes ◽  
Kittipan Rerkasem ◽  
Nikolaos Papanas
Keyword(s):  
Blood Flow ◽  
Optical Coherence Tomography ◽  
Blood Vessel ◽  
Chronic Wounds ◽  
Vessel Density ◽  
Optical Coherence ◽  
Skin Microcirculation ◽  
Wound Edge ◽  
Venous Ulcers ◽  
Oct Imaging

Dynamic optical coherence tomography (D-OCT) is a relatively new technique that may be used to study the substructures in the retina, in the skin and its microcirculation. Furthermore, D-OCT is a validated method of imaging blood flow in skin microcirculation. The skin around venous and mixed arterio-venous ulcers was imaged and found to have tortuous vessels assumed to be angiogenic sprouts, and classified as dots, blobs, coils, clumps, lines, and curves. When these images were analyzed and measurements of vessel density were made, it was observed that the prevalence of coils and clumps in wound borders was significantly greater compared with those at wound centers. This reinforced the belief of inward growth of vessels from wound edge toward wound center which, in turn, reposed confidence in following the wound edge to study healing. D-OCT imaging permits the structure and the function of the microcirculation to be imaged, and vessel density measured. This offers a new vista of skin microcirculation and using it, to better understand angiogenesis in chronic wounds.

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