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

• DOI: 10.1016/j.phrs.2021.105813
• Publication Date: 2021-08-16T15:30:51Z
• Authors: Simone R. Potje; Ayman Isbatan; Rita C. Tostes; Lusiane M. Bendhack; Randal O. Dull; Joao L. Carvalho-...; Andreia Z. Chignalia
• Keywords: Syndecan 1; Calcium Signaling; Pathophysiology of hypertension

Background– Vascular dysfunction is a checkpoint to the development of hypertension. Heparan sulfate proteoglycans (HSPG) participate in nitric oxide (NO) production and calcium signaling, key regulators of vascular function. The relationship between HSPG and vascular dysfunction associated to impaired -NO and calcium signaling 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 systemic blood pressure that is presented in a striking manner in the Gpc1-/- strain. Gpc1-/- has uniquely shown to be protected from a norepinephrine hypertensive challenge failing to become hypertensive. This phenotype was associated with impaired calcium-induced vasoconstriction, exquisitely dependent on exogenous calcium, and altered expression of calcium-sensitive proteins including SERCA and calmodulin. In addition, Gpc1-/- distinctively showed decreased IP3R activity and reduced 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.