Accuracy, precision, and interobserver and intraobserver agreements related to pressure-measurement devices.

OBJECTIVE: To evaluate the accuracy, precision, and observer agreement of three pressure measurement devices. STUDY DESIGN: In vitro model study. SAMPLE POPULATION: Water manometer with built-in gauge (WMg), arterial pressure transducer (APT), and Compass CT (CCT). METHODS: The model was set to five predetermined pressures (4, 8, 13, 17, and 24 cm H2 O) using a water manometer with a ruler (WMr) as the gold standard. Each device was tested at each pressure in a randomized order by three investigators. Bland-Altman plots were used to assess agreement between devices. Intraclass correlation coefficients (ICC) were calculated for interobserver and intraobserver agreements. RESULTS: The mean differences (cm H2 O) ± SEM in comparison with the set pressure were -0.020 ± 0.010 (WMg), -0.390 ± 0.077 (APT), and -1.267 ± 0.213 (CCT). Pressures measured by WMg did not differ from those measured by WMr. Pressures measured by all devices did not differ from each other (p > .062 for all comparisons). Interobserver agreement was excellent (1.000), and intraobserver agreement was excellent (0.985, 0.990, 0.998 for each observer). CONCLUSION: Compared to the WMr, the WMg was the most accurate and precise, followed by the APT; the CCT was the least accurate and precise. Interobserver and intraobserver agreements for all three devices were excellent. CLINICAL SIGNIFICANCE: The largest mean difference of all devices was within 1.3 cm H2 O of the set pressure, indicating possible clinical utility of any of the devices. However, WMr or WMg should be considered first due to their high precision and accuracy.

Surgical and oncologic outcomes in dogs with malignant peripheral nerve sheath tumours arising from the brachial or lumbosacral plexus.

Malignant peripheral nerve sheath tumours (MPNST) of a plexus nerve or nerve root cause significant morbidity and present a treatment challenge. The surgical approach can be complex and information is lacking on outcomes. The objective of this study was to describe surgical complication rates and oncologic outcomes for canine MPNST of the brachial or lumbosacral plexus. Dogs treated for a naïve MPNST with amputation/hemipelvectomy with or without a laminectomy were retrospectively analysed. Oncologic outcomes were disease free interval (DFI), overall survival (OS), and 1- and 2-year survival rates. Thirty dogs were included. The surgery performed was amputation alone in 17 cases (57%), and amputation/hemipelvectomy with laminectomy in 13 cases (43%). Four dogs (13%) had an intraoperative complication, while 11 dogs (37%) had postoperative complications. Histologic margins were reported as R0 in 12 dogs (40%), R1 in 12 dogs (40%), and R2 in five dogs (17%). No association was found between histologic grade and margin nor extent of surgical approach and margin. Thirteen dogs (46%) had recurrence. The median DFI was 511 days (95% CI: 140-882 days). The median disease specific OST was 570 days (95% CI: 467-673 days) with 1- and 2-year survival rates of 82% and 22% respectively. No variables were significantly associated with recurrence, DFI, or disease specific OST. These data show surgical treatment of plexus MPNST was associated with a high intra- and postoperative complication rate but relatively good disease outcomes. This information can guide clinicians in surgical risk management and owner communication regarding realistic outcomes and complications.

Adrenal tumors treated by adrenalectomy following spontaneous rupture carry an overall favorable prognosis: retrospective evaluation of outcomes in 59 dogs and 3 cats (2000-2021).

OBJECTIVE: To conduct a retrospective multi-institutional study reporting short- and long-term outcomes of adrenalectomy in patients presenting with acute hemorrhage secondary to spontaneous adrenal rupture. ANIMALS: 59 dogs and 3 cats. METHODS: Medical records of dogs and cats undergoing adrenalectomy between 2000 and 2021 for ruptured adrenal masses were reviewed. Data collected included clinical presentation, preoperative diagnostics, surgical report, anesthesia and hospitalization findings, histopathology, adjuvant treatments, and long-term outcome (recurrence, metastasis, and survival). RESULTS: Median time from hospital admission to surgery was 3 days, with 34% of surgeries being performed emergently (within 1 day of presentation). Need for intraoperative blood transfusion was significantly associated with emergent surgery and presence of active intraoperative hemorrhage. The short-term (≤ 14 days) complication and mortality rates were 42% and 21%, respectively. Negative prognostic factors for short-term survival included emergent surgery, intraoperative hypotension, and performing additional surgical procedures. Diagnoses included adrenocortical neoplasia (malignant [41%], benign [12%], and undetermined [5%]), pheochromocytoma (38%), a single case of adrenal fibrosis and hemorrhage (2%), and a single case of hemangiosarcoma (2%). Local recurrence and metastasis of adrenocortical carcinoma were confirmed in 1 and 3 cases, respectively. Overall median survival time was 574 days and 900 days when short-term mortality was censored. No significant relationship was found between histopathological diagnosis and survival. CLINICAL RELEVANCE: Adrenalectomy for ruptured adrenal gland masses was associated with similar short- and long-term outcomes as compared with previously reported nonruptured cases. If hemodynamic stability can be achieved, delaying surgery and limiting additional procedures appear indicated to optimize short-term survival.

Long-term outcomes associated with a modified versus traditional closed anal sacculectomy for treatment of canine anal sac neoplasia.

OBJECTIVE: To report the short-term and long-term outcomes of dogs that underwent the modified closed and traditional closed anal sacculectomy procedures for the treatment of anal sac neoplasia. ANIMALS: 90 client-owned dogs. Methods: The medical records of 2 tertiary referral hospitals were reviewed to identify dogs that underwent anal sacculectomy for treatment of anal sac neoplasia between January 2016 and December 2020. Data collected included signalment and preoperative diagnostic findings. The occurrence of intraoperative and postoperative complications, short-term outcomes, and long-term outcomes were also collected. Descriptive statistics were calculated to summarize dog signalment information, and recurrence, metastasis, and survival proportions were compared between techniques using Fisher exact tests. RESULTS: 35 and 55 dogs, respectively, underwent the modified or traditional closed anal sacculectomy procedure. Minor postoperative complications that resolved with minimal intervention occurred in 5 of 35 (14.3%) modified approach dogs and 12 of 55 (21.8%) traditional approach dogs. Tumor recurrence was confirmed in 8 of 35 (22.9%) modified and 8 of 55 (26.4%) traditional approach dogs and was suspected in 3 of 35 (8.6%) and 6 of 55 (13.2%; P = .68), respectively. Confirmed metastatic disease was identified in 8 of 35 (22.9%) and 14 of 53 (26.4%) modified and traditional approach dogs, respectively, and was suspected in 4 of 35 (11.4%) and 7 of 53 (13.2%). Sixty-three (70%) dogs survived to study conclusion. CLINICAL RELEVANCE: No benefits in complication rate or local recurrence were identified in dogs following the modified approach as opposed to the traditional closed anal sacculectomy technique.

Conditional expression of endorepellin in the tumor vasculature attenuates breast cancer growth, angiogenesis and hyaluronan deposition.

The tumor stroma of most solid malignancies is characterized by a pathological accumulation of pro-angiogenic and pro-tumorigenic hyaluronan driving tumorigenesis and metastatic potential. Of all three hyaluronan synthase isoforms, HAS2 is the primary enzyme that promotes the build-up of tumorigenic HA in breast cancer. Previously, we discovered that endorepellin, the angiostatic C-terminal fragment of perlecan, evokes a catabolic mechanism targeting endothelial HAS2 and hyaluronan via autophagic induction. To explore the translational implications of endorepellin in breast cancer, we created a double transgenic, inducible Tie2CreERT2;endorepellin(ER)Ki mouse line that expresses recombinant endorepellin specifically from the endothelium. We investigated the therapeutic effects of recombinant endorepellin overexpression in an orthotopic, syngeneic breast cancer allograft mouse model. First, adenoviral delivery of Cre evoking intratumor expression of endorepellin in ERKi mice suppressed breast cancer growth, peritumor hyaluronan and angiogenesis. Moreover, tamoxifen-induced expression of recombinant endorepellin specifically from the endothelium in Tie2CreERT2;ERKi mice markedly suppressed breast cancer allograft growth, hyaluronan deposition in the tumor proper and perivascular tissues, and tumor angiogenesis. These results provide insight into the tumor suppressing activity of endorepellin at the molecular level and implicate endorepellin as a promising cancer protein therapy that targets hyaluronan in the tumor microenvironment.

Retrospective Study Evaluating Surgical Treatment and Outcome in Dogs with Septic Peritonitis Secondary to Neoplasia.

Septic peritonitis is a life-threatening disease that can be caused by neoplasia, among other disease processes. There is no veterinary literature directly evaluating the outcome of patients with septic peritonitis caused by neoplasia. The objective of this study was to evaluate for differences in survival to discharge and complication rates between septic peritonitis caused by neoplastic and nonneoplastic disease in canine patients. A single-institution retrospective cross-sectional cohort study was performed, identifying dogs that were treated surgically for septic peritonitis between January 1, 2010, and November 1, 2020. A total of 86 patients were included, 12 with a neoplastic cause for septic peritonitis and 74 with another cause. The most common neoplastic lesions associated with septic peritonitis were gastrointestinal lymphoma and hepatocellular adenoma. Presence of neoplasia was not a significant factor for development of intraoperative or immediate postoperative complications, nor did it decrease chances of survival to discharge (P < .09). The diagnosis of a primary, localized, neoplastic lesion alone should not deter clinicians and owners from pursuing treatment for septic peritonitis.

Clinical presentation and outcome in cats with aural squamous cell carcinoma: a review of 25 cases (2010-2021).

CASE SERIES SUMMARY: Ear canal neoplasia is uncommon in cats. Ceruminous gland adenocarcinoma is the most frequently reported malignant neoplasm of the feline ear canal, and squamous cell carcinoma (SCC) is the most common malignant neoplasm diagnosed in the feline middle ear. However, limited information exists on the outcome of cats diagnosed with SCC of the ear canal, middle or inner ear. Therefore, the objective of this study was to describe the outcome of cats diagnosed with SCC affecting these locations. Medical records were reviewed at multiple institutions to identify cats with a definitive diagnosis of SCC. Twenty-five cats were identified. Eleven cats were treated with surgery, eight with medical management, two with coarse fractionated radiation therapy, two with a combination of coarse fractionated radiation therapy and chemotherapy, one with a combination of surgery and coarse fractionated radiation therapy, one cat with systemic chemotherapy and one cat received no treatment following diagnosis. The median survival time of cats treated with surgery was 168 days vs 85 days (P = 0.28) for those treated palliatively with either medical management, radiation therapy, chemotherapy, or a combination of radiation therapy and chemotherapy. RELEVANCE AND NOVEL INFORMATION: This case series documented that SCC of the ear canal, middle and/or internal ear is a locally aggressive tumor that carries an overall poor prognosis. The median survival time for cats treated with surgery was longer than that with any other modality, but this difference was not statistically significant.

Optical coherence tomography for surgical margin evaluation of excised canine cutaneous and subcutaneous tumours.

Currently, intraoperative tumour margin imaging is not routinely utilized in veterinary medicine. Optical coherence tomography (OCT) allows for real-time assessment of tissue morphology of 1-2 mm depth. The aims of this study were (1) to compare the histologic and OCT features of excised canine skin and subcutaneous specimens, and (2) to determine the diagnostic accuracy of OCT for surgical margin evaluation. The authors hypothesized that OCT imaging would correlate well with histopathology and that OCT would be sensitive for detection of incomplete margins. Eighty dogs were prospectively enrolled. Tumours were excised, and the surgical margins were imaged using a spectral domain OCT system. The tumour type and completeness of excision were determined by histopathology. Nine blinded observers received training in OCT image interpretation and were then given a set of OCT images and videos. The observers assigned each image/video a grade from 1 (no tumour) to 4 (tumour) and the results were compared to histopathology. The overall median sensitivity and specificity of OCT imaging for detection of incomplete margins were 86.7% and 84.6%, respectively. A potential limitation is that observers had varied experience with OCT image interpretation, ranging from no prior experience to participating in a previous OCT project. OCT is sensitive for detection of incomplete margins and could be a promising real-time surgical margin imaging modality. Further study is needed to evaluate intraoperative applications of OCT and its impact on tumour recurrence and long-term outcome.

Risk factors and outcome in dogs with recurrent massive hepatocellular carcinoma: A Veterinary Society of Surgical Oncology case-control study.

Local recurrence after surgical excision of canine massive hepatocellular carcinoma (HCC) has been poorly studied in veterinary medicine with scant information published regarding risk factors for and outcome following recurrence. The aim of this case-control study was to describe the time to recurrence, evaluate potential risk factors for recurrence, and report the outcome in dogs with massive HCC. Medical records for 75 dogs who developed recurrence and 113 dogs who did not develop recurrence were reviewed. Statistical analyses were performed to determine risk factors for recurrence as well as the median time to develop recurrence and overall survival time (OS). None of the risk factors evaluated were significant for the development of recurrence. The median time to develop recurrence was 367 days (range 32-2096 days). There was no significant difference in median OS for dogs who developed recurrence vs. those who did not (851 vs. 970 days). For dogs with recurrent HCC, treatment at recurrence trended toward prolonged OS but was not significantly different from dogs not undergoing treatment at recurrence. There was no significant difference in median OS for dogs with histologically complete vs. incomplete tumour excision (990 vs. 903 days). Although specific risk factors for recurrence were not identified, elevations in liver values were noted in patients with recurrent disease and could act as a noninvasive surveillance tool. Recurrence was noted earlier in dogs who had routine post-operative surveillance (228 vs. 367 days). Routine surveillance for recurrence is recommended especially in dogs where further intervention is possible and should extend beyond 1 year. Patients with massive HCC have a good long-term prognosis regardless of incomplete excision, pulmonary metastasis, or recurrent local disease.

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth.

The extracellular matrix (ECM) exists as a dynamic network of biophysical and biochemical factors that maintain tissue homeostasis. Given its sensitivity to changes in the intra- and extracellular space, the plasticity of the ECM can be pathological in driving disease through aberrant matrix remodelling. In particular, cancer uses the matrix for its proliferation, angiogenesis, cellular reprogramming and metastatic spread. An emerging field of matrix biology focuses on proteoglycans that regulate autophagy, an intracellular process that plays both critical and contextual roles in cancer. Here, we review the most prominent autophagic modulators from the matrix and the current understanding of the cellular pathways and signalling cascades that mechanistically drive their autophagic function. We then critically assess how their autophagic functions influence tumorigenesis, emphasizing the complexities and stage-dependent nature of this relationship in cancer. We highlight novel emerging data on immunoglobulin-containing and proline-rich receptor-1, heparanase and thrombospondin 1 in autophagy and cancer. Finally, we further discuss the pro- and anti-autophagic modulators originating from the ECM, as well as how these proteoglycans and other matrix constituents specifically influence cancer progression.

Minimal complications observed with a modified surgical approach for treatment of canine anal sac neoplasia.

OBJECTIVE: To describe a modified approach to closed anal sacculectomy and report the short-term outcomes of dogs that underwent the procedure for treatment of neoplasia. ANIMALS: 16 client-owned dogs. PROCEDURES: Medical records of 1 referral hospital were reviewed to identify dogs that underwent modified closed anal sacculectomy for treatment of anal sac neoplasia between January 2018 and September 2020. Data collected included signalment, examination and diagnostic imaging findings, surgical details, intraoperative and postoperative complications, cytologic and histologic findings, adjuvant treatments, duration of follow-up, and short-term outcome. RESULTS: 15 dogs had apocrine gland anal sac adenocarcinoma, and 1 had a collision tumor. No dogs had intraoperative complications; 1 dog had a minor postoperative complication (paraparesis) that resolved. The median duration of postoperative follow-up was 286 days (range, 67 to 777 days). One dog had confirmed local disease recurrence 290 days after surgery, and 1 had suspected local disease recurrence 203 days after surgery and was euthanized because of systemic disease progression. CONCLUSIONS AND CLINICAL RELEVANCE: The modified closed anal sacculectomy was well tolerated in this sample of dogs, with minimal short-term complications. This study provided evidence to justify evaluation of the procedure in a larger number of dogs and assessment of the effects of procedural modifications on postoperative complication rates and time to local recurrence.

Analysis of risk factors associated with complications following mandibulectomy and maxillectomy in dogs.

OBJECTIVE: To provide information about complication rates and the risk factors for complications with mandibulectomy and maxillectomy procedures in dogs. ANIMALS: 459 client-owned dogs that underwent a mandibulectomy or maxillectomy between January 1, 2007, and January 1, 2018. PROCEDURES: Inclusion criteria included a complete medical record that contained an anesthesia record, surgical report, available histopathology results, and results of CBC and serum biochemical analysis before surgery. A minimum follow-up of 90 days after surgery was required. RESULTS: 271 complications occurred in 171 of 459 (37.3%) dogs. Eighteen complications were not given a severity description. Of the remaining 253 complications, most were considered minor (157/253 [62.1%]). Multivariable logistic regression analysis revealed that only increased surgical time had a significant (OR, 1.36; 95% CI, 1.12 to 1.54) association with the occurrence of ≥ 1 complication. For each additional hour of surgery, the odds of complications increased by 36%. Preoperative radiation therapy or chemotherapy increased the odds of incisional dehiscence or oral fistula formation (OR, 3.0; 95% CI, 1.3 to 7.2). Additionally, undergoing maxillectomy, compared with mandibulectomy, increased the odds of incisional dehiscence or oral fistula formation (OR, 1.8; 95% CI, 1.1 to 3.1). Two hundred forty-four of 271 (90.0%) complications occurred in the perioperative period (0 to 3 months after surgery). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with mandibulectomy, performing maxillectomy increased the risk for incisional dehiscence or oral fistula formation. Mandibulectomy and maxillectomy had a moderate risk for a complication.

Case Report: Use of PET/CT to Guide Treatment in a Cat With Presentation Consistent With Hodgkin's-Like Lymphoma.

An 8-year-old male neutered Domestic Long Hair cat was presented for a cervical swelling that was suspected to be an enlarged left retropharyngeal lymph node. In the absence of other lymphadenopathy, this was initially suspected to be Hodgkin's-like lymphoma. A positron emission tomography-computed tomography (PET/CT) scan was performed using 2-deoxy-2-[18F]-fluorodeoxyglucose (18F-FDG) to assess for evidence of disease in other locations to guide treatment. Multifocal increased radiopharmaceutical uptake was identified, indicating disease in multiple organs. High-grade lymphoma was confirmed on tissue biopsy. As such, systemic cytotoxic chemotherapy was recommended instead of lymph node extirpation surgery. The cat received a modified CHOP chemotherapy protocol and attained a temporary partial remission. After 2 months of treatment, the cat stopped responding to chemotherapy and was eventually euthanized due to a relapse of disease and decreased quality of life. This case describes the utility of PET/CT to guide treatment in a cat with a presentation consistent with Hodgkin's-like lymphoma.

Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology.

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

A Novel Clinical Research Modality for Enrolling Diverse Participants Using a Diverse Team.

The advancement of the pediatric traumatic brain injury (TBI) knowledge base requires biospecimens and data from large samples. This study seeks to describe a novel clinical research modality to establish best practices for enrolling a diverse pediatric TBI population and quantifying key information on enrollment into biobanks. Screening form responses were standardized and cleaned through Google Sheets. Data were used to analyze total individuals at each enrollment stage. R was utilized for final analysis, including logistic model and proportion statistical tests, to determine further significance and relationships. Issues throughout data cleaning shed light on limitations of the consent modality. The results suggest that through a diverse research team, the recruited sample exceeds traditional measures of representation (e.g., sex, race, ethnicity). Sex demographics of the study are representative of the local population. Screening for candidates is critical to the success of the consent modality. The consent modality may be modified to increase the diversity of the study population and accept bilingual candidates. Researchers must implement best practices, including increasing inclusivity of bilingual populations, utilizing technology, and improving participant follow-up, to improve health disparities for understudied clinical populations.

Catabolic degradation of endothelial VEGFA via autophagy.

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells.

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980 Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2-4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7-9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis.

Hyaluronan plays a key role in regulating inflammation and tumor angiogenesis. Of the three transmembrane hyaluronan synthases, HAS2 is the main pro-angiogenic enzyme responsible for excessive hyaluronan production. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy evoked by nutrient deprivation, mTOR inhibition, or pro-autophagic proteoglycan fragments endorepellin and endostatin. Using live-cell and super-resolution confocal microscopy, we found that protracted autophagy evoked a dynamic interaction between HAS2 and ATG9A, a key transmembrane autophagic protein. This regulatory axis of HAS2 degradation occurred in various cell types and species and in vivo upon nutrient deprivation. Inhibiting in vivo autophagic flux via chloroquine showed increased levels of HAS2 in the heart and aorta. Functionally, autophagic induction via endorepellin or mTOR inhibition markedly suppressed extracellular hyaluronan production in vascular endothelial cells and inhibited ex vivo angiogenic sprouting. Thus, we propose autophagy as a novel catabolic mechanism regulating hyaluronan production in endothelial cells and demonstrate a new link between autophagy and angiogenesis that could lead to potential therapeutic modalities for angiogenesis.