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During a 3‐year time period, a 15‐year‐old male castrated Terrier mix (dog 1) and a 6‐year‐old female spayed Labrador Retriever (dog 2) presented to the North Carolina State Veterinary Hospital with similar blood work abnormalities and no significant physical examination findings. A CBC, chemistry panel, and urinalysis performed on both dogs were relatively unremarkable, other than a marked increase in serum gamma‐glutamyltransferase (GGT) activity. Through imaging, both patients were diagnosed with a renal mass, and histopathology of both masses revealed a carcinoma. Immunohistochemical staining of the renal mass in both dog 1 and dog 2 were intensely positive for GGT. Dog 1 had the affected kidney removed, which normalized the GGT value. Dog 2 was euthanized, and metastasis to the lung was noted upon postmortem examination. There have been limited case studies documenting an elevation in serum GGT in dogs diagnosed with renal carcinoma. While renal carcinoma is uncommon in dogs, it is an important differential to keep in mind when there is a marked increase in serum GGT without accompanying increases in other measured liver enzymes. In addition, serum GGT can serve as a helpful biomarker for disease resolution and recurrence, as surgical removal of the renal mass (dog 1) led to the resolution of the elevated serum GGT. To our knowledge, this is the first report demonstrating IHC staining for GGT in a canine renal carcinoma. [ABSTRACT FROM AUTHOR]

Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals. CLEC2-deficient animals exhibited normal growth of the primary mesenteric lymphatic plexus but failed to form valves in these vessels or remodel them into a structured, hierarchical network. Smooth muscle cell coverage (SMC coverage) of CLEC2-deficient lymphatic vessels was both premature and excessive, a phenotype identical to that observed with loss of the lymphatic endothelial transcription factor FOXC2. In vitro evaluation of lymphatic endothelial cells (LECs) revealed that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development and identified GATA2 as an upstream transcriptional regulator of FOXC2 and the lymphatic valve genetic program. These studies reveal that lymph flow initiates and regulates many of the key steps in collecting lymphatic vessel maturation and development., Introduction The lymphatic vascular system regulates tissue fluid homeostasis, immune cell trafficking, and the absorption of dietary fats (1). Lymphatic capillaries lack basement membranes and maintain openings between endothelial cells [...]

Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life., Introduction The mammalian cardiovascular system is divided into distinct blood and lymphatic vascular networks: blood is transported to the tissues in a closed, high-pressure vascular system, and interstitial fluid is [...]

A transmembrane O-glycoprotein podoplanin (PDPN) expressed on fibroblastic reticular cells is the activating ligand for platelet receptor CLEC-2; this interaction leads to perivenular release of sphingosine-1-phosphate and expression of VE-cadherin on high endothelial venules, a key process for the maintenance of vascular integrity in lymph nodes. Role of podoplanin in lymph node homeostasis The lymph nodes, essential sites for immune responses, are supplied with circulating lymphocytes that enter via specialized post-capillary blood vessels known as high endothelial venules (HEVs). How the integrity of this vascular barrier is maintained in the face of the increase in lymphocyte homing during immune responses is not known. Lijun Xia and colleagues now show that the mechanism involves cross-talk between HEVs, platelets and the fibroblastic reticular cells (FRCs) that surround the HEVs. The transmembrane protein podoplanin, expressed on FRCs, interacts with the platelet activation receptor CLEC-2, prompting the release of sphingosine-1-phosphate that in turn preserves the adhesion molecule VE-cadherin on the HEVs. This finding may suggest new approaches to the regulation of lymph node homeostasis in conditions of increased HEV proliferation, such as chronic inflammation. Circulating lymphocytes continuously enter lymph nodes for immune surveillance through specialized blood vessels named high endothelial venules.sup.1,2,3,4,5, a process that increases markedly during immune responses. How high endothelial venules (HEVs) permit lymphocyte transmigration while maintaining vascular integrity is unknown. Here we report a role for the transmembrane O-glycoprotein podoplanin (PDPN, also known as gp38 and T1[alpha]).sup.6,7,8 in maintaining HEV barrier function. Mice with postnatal deletion of Pdpn lost HEV integrity and exhibited spontaneous bleeding in mucosal lymph nodes, and bleeding in the draining peripheral lymph nodes after immunization. Blocking lymphocyte homing rescued bleeding, indicating that PDPN is required to protect the barrier function of HEVs during lymphocyte trafficking. Further analyses demonstrated that PDPN expressed on fibroblastic reticular cells.sup.7, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2, also known as CLEC1B).sup.9,10. Mice lacking fibroblastic reticular cell PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (also known as CDH5), which is essential for overall vascular integrity.sup.11,12, on HEVs. Infusion of wild-type platelets restored HEV integrity in Clec-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate.sup.13,14 from platelets, which promoted expression of VE-cadherin on HEVs ex vivo. Furthermore, draining peripheral lymph nodes of immunized mice lacking sphingosine-1-phosphate had impaired HEV integrity similar to Pdpn- and Clec-2-deficient mice. These data demonstrate that local sphingosine-1-phosphate release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses., Author(s): Brett H. Herzog [sup.1] [sup.2] , Jianxin Fu [sup.1] [sup.3] [sup.4] , Stephen J. Wilson [sup.5] , Paul R. Hess [sup.6] , Aslihan Sen [sup.6] , J. Michael McDaniel [...]

Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway., Introduction Platelets play an essential role in the prevention of excessive blood loss after injury (hemostasis), but can also form occlusive thrombi at sites of atherosclerotic plaque rupture (thrombosis) (1). [...]