Glypican 1 and syndecan 1 differently regulate noradrenergic hypertension development: Focus on IP3R and calcium

Author(s)

Potje, Simone R. ^{[1, 2, 3, 4]} ; Isbatan, Ayman ^[4] ; Tostes, Rita C. ^[1] ; Bendhack, Lusiane M. ^[2] ; Dull, Randal O. ^{[3, 5, 6]} ; Carvalho-de-Souza, Joao L. ^{[3, 5]} ; Chignalia, Andreia Z. ^{[3, 5, 7]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, Ribeirao Preto - Brazil

^[3] Univ Arizona, Coll Med Tucson, Dept Anesthesiol, 1501 N Campbell Rd, Suite 4401, Tucson, AZ 85724 - USA

^[4] Univ Illinois, Coll Med, Dept Anesthesiol, Chicago, IL 60680 - USA

^[5] Univ Arizona, Coll Med Tucson, Dept Physiol, Tucson, AZ 85724 - USA

^[6] Univ Arizona, Coll Med Tucson, Dept Pathol, Tucson, AZ 85724 - USA

^[7] Univ Arizona, Coll Pharm Tucson, Dept Pharmacol & Toxicol, Tucson, AZ 85724 - USA

• Document type: Journal article
• Source: PHARMACOLOGICAL RESEARCH; v. 172, OCT 2021.
• Web of Science Citations: 0

Abstract

Background: Vascular dysfunction is a checkpoint to the development of hypertension. Heparan sulfate proteoglycans (HSPG) participate in nitric oxide (NO) and calcium signaling, key regulators of vascular function. The relationship between HSPG-mediated NO and calcium signaling and vascular dysfunction has not been explored. Likewise, the role of HSPG on the control of systemic blood arterial pressure is unknown. Herein, we sought to determine if the HSPG syndecan 1 and glypican 1 control systemic blood pressure and the progression of hypertension. Purpose: To determine the mechanisms whereby glypican 1 and syndecan 1 regulate vascular tone and contribute to the development of noradrenergic hypertension. Experimental approach and key results: By assessing systemic arterial blood pressure we observed that syndecan 1 (Sdc1(-/-)) and glypican 1 (Gpc1(-/-)) knockout mice show a similar phenotype of decreased systolic blood pressure that is presented in a striking manner in the Gpc1(-/-) strain. Gpc1(-/-) mice are also uniquely protected from a norepinephrine hypertensive challenge failing to become hypertensive. This phenotype was associated with impaired calcium-dependent vasoconstriction and altered expression of calcium-sensitive proteins including SERCA and calmodulin. In addition, Gpc1(-/-) distinctively showed decreased IP3R activity and increased calcium storage in the endoplasmic reticulum. Conclusions and implications: Glypican 1 is a trigger for the development of noradrenergic hypertension that acts via IP3R- and calcium-dependent signaling pathways. Glypican 1 may be a potential target for the development of new therapies for resistant hypertension or conditions where norepinephrine levels are increased. (AU)

• FAPESP's process: 19/06653-2 - Heparan sulfate proteoglycans as regulators of vascular tone
• Grantee: Simone Regina Potje
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 18/01853-0 - The mechanotransduction pathways activated by increased intravascular pressure in glypican-1 and syndecan-1 knockout mice
• Grantee: Simone Regina Potje
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor