Richard Minshall

Using genetic in vivo and in vitro approaches, disease models, and human tissues, we are determining whether caveolin-1 expression level and post-translational modification participates in the regulation of lung vascular homeostasis and in the etiology of lung diseases. Our goal is to determine whether this basic information can be used to develop novel therapeutic approaches for treating inflammatory and remodeling lung diseases. Current research projects are characterizing the role of caveolin-1 in the regulation of 1) transcellular vesicular transport and lung fluid homeostasis, 2) leukocyte recruitment and transmigration initiated by cell surface adhesion molecule activation, 3) lung microvascular endothelial cell differentiation and angiogenesis, and 4) distal lung epithelial progenitor cell differentiation and lung development. In these studies, we have shown that caveolin-1 plays an essential role in the regulation of Src, dynamin-2, and eNOS signaling, and that downstream phosphorylation and nitrosation events regulate caveolin-1 expression, caveolae-mediated endocytosis, angiogenesis, vascular tone, and inflammation. Furthermore, endothelial cell function and inflammation-evoked endothelial hyperpermeability measured in Cav1-/-, eNOS-/-, and double knockout mice as well as isolated lung microvascular endothelial cells and expression systems is revealing feed-back and feed-forward mechanisms of caveolin-1 regulated eNOS and Src signaling. For example, we have shown that NO-mediated Src activation provides a negative feedback mechanism to inactivate eNOS and Src which is mediated by phospho-caveolin-1 dependent sequestration of eNOS as well as recruitment of Csk, the Src inactivating kinase. The clinical importance of these observations is suggested by studies which link reduced Cav-1 expression to eNOS-dependent ROS production, sustained Src activation, disruption of endothelial monolayer integrity, aberrant angiogenesis, and increased pulmonary vascular resistance associated with pulmonary arterial hypertension. In a similar manner, we have observed that ICAM-1 activation-dependent NO and O2- production induces Src-dependent caveolin-1 and dynamin-2 phosphorylation, caveolae-mediated transcellular protein transport, and leukocyte transmigration. Thus, Cav-1 expression, via regulation of eNOS and Src signaling, is an important determinant of host defense and inflammation-induced vascular injury.

Oliveira SD, Castellon M, Chen J, Bonini MG, Gu X, Elliott MH, Machado RF, Minshall RD. Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGFβ-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2017 Feb 10:ajplung.00484.2016.

Jiang Y, Sverdlov MS, Toth PT, Huang LS, Du G, Liu Y, Natarajan V, Minshall RD. Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. J Biol Chem. 2016 Sep 23;291(39):20729-38.

Zimnicka AM, Husain YS, Shajahan AN, Sverdlov M, Chaga O, Chen Z, Toth PT, Klomp J, Karginov AV, Tiruppathi C, Malik AB, Minshall RD. Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae. Mol Biol Cell. 2016 Jul 1;27(13):2090-106.

Bakhshi FR, Mao M, Shajahan AN, Piegeler T, Chen Z, Chernaya O, Sharma T, Elliott WM, Comhair S, Erzurum S, van NieuwAmerongen GP, Bonini MG, Minshall RD. Nitrosation-dependent caveolin-1 phosphorylation, ubiquitination, and degradation and its association with idiopathic pulmonary arterial hypertension. Pulm Circ. (Cover Image). In Press.

Rusu L, Andreeva A, Visintine DJ, Kim K, Vogel SM, Stojanovic-Terpo A, Chernaya O, Liu G, Bakhshi FR, Haberichter SL, Iwanari H, Kusano-Arai O, Suzuki N, Hamakubo T, Kozasa T, Cho J, Du X, Minshall RD. G protein-dependent basal and evoked endothelial cell vWF secretion. Blood. 123:442-50, 2014. (Editorial; Cover image)

Liu G, Place AT, Chen Z, Brovkovych VM, Vogel SM, Muller WA, Skidgel RA, Malik AB, Minshall RD. ICAM-1 activated Src and NO signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration. Blood.120:1942-52, 2012.

Chen Z, Bakhshi F, Shajahan AN, Mao M, Trane A, Sharma T, Bernatchez P, van NieuwAmerongen GP, Bonini M, Skidgel RA, Malik AB, Minshall RD. Nitric oxide-dependent Src activation and caveolin-1 phosphorylation promotes eNOS/Cav-1 binding and eNOS inhibition. Mol Biol Cell. 23:1388-1398, 2012.