Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues.

Fibrillin microfibrils play a critical role in the formation of elastic fibers, tissue/organ development, and cardiopulmonary function. These microfibrils not only provide structural support and flexibility to tissues, but they also regulate growth factor signaling through a plethora of microfibril-binding proteins in the extracellular space. Mutations in fibrillins are associated with human diseases affecting cardiovascular, pulmonary, skeletal, and ocular systems.

Multi-organ phenotypes in mice lacking latent TGFβ binding protein 2 (LTBP2).

Background: Latent TGFβ binding protein-2 (LTBP2) is a fibrillin 1 binding component of the microfibril. LTBP2 is the only LTBP protein that does not bind any isoforms of TGFβ, although it may interfere with the function of other LTBPs or interact with other signaling pathways.

Results: Here, we investigate mice lacking Ltbp2 (Ltbp2 ) and identify multiple phenotypes that impact bodyweight and fat mass, and affect bone and skin development.

A new mouse model of elastin haploinsufficiency highlights the importance of elastin to vascular development and blood pressure regulation.

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disease resulting from elastin (ELN) haploinsufficiency. Individuals with SVAS typically develop a thickened arterial media with an increased number of elastic lamellae and smooth muscle cell (SMC) layers and stenosis superior to the aortic valve. A mouse model of SVAS (Eln) was generated that recapitulates many aspects of the human disease, including increased medial SMC layers and elastic lamellae, large artery stiffness, and hypertension.

Loss of Angiotensin II Type 2 Receptor Improves Blood Pressure in Elastin Insufficiency.

There is ample evidence supporting a role for angiotensin II type 2 receptor (ATR) in counterbalancing the effects of angiotensin II (ang II) through the angiotensin II type 1 receptor by promoting vasodilation and having anti-inflammatory effects. Elastin insufficiency in both humans and mice results in large artery stiffness and systolic hypertension. Unexpectedly, mesenteric arteries from elastin insufficient ( ) mice were shown to have significant vasoconstriction to ATR agonism suggesting that ATR may have vasoconstrictor effects in elastin insufficiency.

Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry.

Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase.

Heterogeneous Cellular Contributions to Elastic Laminae Formation in Arterial Wall Development.

Rationale: Elastin is an important ECM (extracellular matrix) protein in large and small arteries. Vascular smooth muscle cells (SMCs) produce the layered elastic laminae found in elastic arteries but synthesize little elastin in muscular arteries. However, muscular arteries have a well-defined internal elastic lamina (IEL) that separates endothelial cells (ECs) from SMCs.

Nonlinear optical imaging of extracellular matrix proteins.

Over the last 2 decades, nonlinear imaging methods such as multiharmonic imaging microscopy (MHIM) have become powerful approaches for the label-free visualization of biological structures. Multiharmonic signals are generated when an intense electromagnetic field propagates through a sample that either has a specific molecular orientation or exhibits certain physical properties. It can provide complementary morphological information when integrated with other nonlinear optical imaging techniques such as two-photon excitation (TPE).

Inducible Expression of Claudin-1 in Glomerular Podocytes Generates Aberrant Tight Junctions and Proteinuria through Slit Diaphragm Destabilization.

The tight junction (TJ) has a key role in regulating paracellular permeability to water and solutes in the kidney. However, the functional role of the TJ in the glomerular podocyte is unclear. In diabetic nephropathy, the gene expression of claudins, in particular claudin-1, is markedly upregulated in the podocyte, accompanied by a tighter filtration slit and the appearance of TJ-like structures between the foot processes.

Ultrastructural properties of ciliary zonule microfibrils.

Conventional electron microscopy and rotary shadowing techniques have provided conflicting interpretations of microfibril ultrastructure. To address this issue, we have used quick-freeze deep-etch (QFDE) microscopy to obtain 3-dimensional surface views of microfibrils that have not been fixed, dehydrated, or stained with heavy metals. By this approach, microfibrils appear as tightly packed rows of bead-like subunits that do not display the interbead filamentous links seen by other methods.