Abstract
Purpose :
Caveolae are specialized invaginations of the plasma membrane shaped by caveolin-1 (Cav1). Importantly, polymorphisms at the Cav1/2 gene loci impart increased risk for ocular hypertension and primary open angle glaucoma. Cav1 expression by the trabecular meshwork (TM) in endothelial-specific Cav1 deficient mice is sufficient to rescue conventional outflow (CO) defects observed in global Cav1 KO mice, and loss of Cav1 in cultured human TM cells results in a loss of extracellular matrix regulation and an elevation in phosphorylated myosin light chain, a surrogate indicator of contractile tone. Thus, we hypothesize that Cav1 in the TM mediates intraocular pressure (IOP) regulation by serving as mechanosensors to detect and respond to changes in IOP.
Methods :
To examine Cav1 function in the TM, we used a lentivirus (lenti-Cre) to deliver Cre recombinase to TM of homozygous Cav1 floxed (Cav1-\-) mice via intracameral injection. The uninjected contralateral eye served as a naïve control. Wild-type mice not expressing the floxed allele received the same unilateral virus injection and served as a control. IOP was measured by rebound tonometry for 5 weeks post-lenti-Cre injection. After 5 weeks, outflow facility in enucleated eyes was compared between injected eyes of each genotype using the iPerfusion system. Statistical analysis was performed using unpaired t-test.
Results :
IOP was significantly elevated in Cav1-\- mouse eyes at 5 weeks post lenti-Cre injection (19.5 ± 1.3mmHg, n=12), compared to injected wild type mouse eyes (15.9 ± 1.8mmHg, p<0.0001, n=12). Moreover, outflow facility was reduced in Cav1-\- mouse eyes injected with lenti-Cre (1.49 ± 0.8nl/min/mmHg, n=10) as compared to injected wild type mouse eyes (1.96 ± 0.6nl/min/mmHg, n=9) although not significantly (p=0.16). However, if one extraordinarily high facility measurement (3.1nl/min/mmHg) from a Cav1-\- mouse eye with an iris adhesion to the injection site was excluded, facility was significantly reduced in injected Cav1-\- mouse eyes (now 1.31 ± 0.6nl/min/mmHg, n=9) as compared to injected wild type mouse eyes (p=0.03), suggesting IOP elevation is due to increased CO resistance.
Conclusions :
Elevated IOP in global Cav1-deficient mice is in part attributable to loss of caveolae expression in the TM, and caveolae in the TM appear necessary for IOP homeostasis.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.