Separation of Blood and Lymphatic Vascular Networks Is Regulated by the Hematopoietic Signaling Proteins SLP-76 and Syk.
Reviewer: Julie Draznin Maltzman, MD
Last Modified: December 8, 2002
Presenter: Farhad Abtahian Presenter's Affiliation: University of Pennsylvania Type of Session: Plenary
Currently we do not know how blood vessels and lymph vessles form in the fetus.
We do know that they begin their development together and at some stage in the fetal development there are molecular signals that are sent to these primitive cells that instruct them to become either blood vessels or lymph vessels.
These signals are suspected to be the interaction between VEGF (Vascular Endothelial Growth Factor)-- a growth promoting hormone, and tyrosine kinase receptors.
One such tyrosine kinase receptor is Syk. SLP 76 is an adaptor protein that is found with Syk helping it to transmit it's signal inside the cell.
Materials and Methods
Mice were genetically engineered to be missing either SLP-76 or Syk.
Since these molecules are found only in hematopeoitic cells the WBC, RBCs, and PLTs of these mice were studied.
These mice did have a lymphocyte development defect. In the process of this work it was noted that the blood vessels from these mutant mice were fragile and tore easily giving the mice a bleeding defect.
Fetal mutant mice were examined at various embryonic stages and their vessels were stained with either immunohistochemical stains or with fluorescent microspheres. The latter are tiny beads that are large enough to pass through an arteriol but not large enough to pass through a capillary bed. By using these microspheres the investigators were able to visualise any arterio-venous malformations (AVM).
The small bowel of these mutant mice was analysed microscopically for any evidence of any AVM's.
Cardiac MRI's were done on these mutant mice for characterization and analysis of cardiac output and overall cardiac function.
Bone marrows derived from mice who are deficient in either Slp-76 or Syk were transplanted into mice whose own bone marrow was irradiated.
SLP-76 or Syk deficient mice had hearts that were 40% larger than the control non mutant animals.
This increase in heart size was not associated with cardiac malfunction but rather an increase in cardiac output.
Since these mice are not anemic the other possible reason for such a high cardiac output was AVM develpment.
Indeed microscopic analysis of the gut did reveal multiple AVMs through out the bowel.
MIcrospoheres showed multiple AVMs through the body, predominating in the gut and liver.
Immunohistochemistry showed that vessels were filled with both blood and lymph in the embroynic mutant mice.
Adult mice who underwent a bone marrow transplant with mutant bone marrows developed AVM's in adulthood.
Slp-76 and Syk are neccessary to form distinct blood and lymph vessels.
Slp-76 and Syk are both required in the signaling pathway of vessel differentiation in utero.
SLP-76 and Syk deficiency leads to a primary vascular defect.
These data have implications beyond embryology in that modulation of angiogenesis is now a true potential.
By modulating formation of new blood vessels there is potential to alter tumor gowth/development.
Many studies are ongoing to utilize angiogenesis inhibitors in the treatment of cancer.
This study has identified SLP-76 and Syk as potential targets to alter blood vessel formation in tumors.
Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Ortho Biotech.
Jun 20, 2012 - Targeting the hedgehog signaling pathway with a smoothened antagonist, GDC-0449, in combination with gemcitabine achieves partial response in some metastatic pancreatic cancer patients; and targeted depletion of the multi-functional cell membrane protein RLIP76 can cause pancreatic cancer tumors in mice to regress, according to two studies presented at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held from June 18 to 21 in Lake Tahoe, Nev.