Most people generally understand that chronic high blood sugar isn’t a good thing. But why exactly isn’t it? I’ve posed this question before, and the overwhelming response is that it leads to type 2 diabetes. That isn’t really answering the question, is it? Here, I’ll briefly discuss one potential answer to this question by exploring how high blood sugar causes irregularities in cellular function. Specifically, we’ll see how hyperglycemia alters the function of vascular smooth muscle, thereby contributing to an increase in blood pressure.
Some basic points to know to make sense of the content further down in this post:
- Blood Pressure = Cardiac Output x Total Peripheral Resistance.
- Cardiac output is calculated by multiplying your heart rate by total stroke volume (the amount of blood ejected from the heart).
- Total peripheral resistance is the resistance to blood flow by all the vasculature in your body. It’s determined mostly by changes to the radius of the blood vessels, but the viscosity of your blood also contributes a bit.
Inflammation and hyperglycemia-induced cell signaling dysfunction result in vascular smooth muscle contractile hyperreactivity.
When you’re healthy, the pro-inflammatory enzyme COX-2 isn’t detectable in vascular smooth muscle (VSM). Under hyperglycemic conditions, and especially type 2 diabetes (T2DM), COX-2 expression in the VSM increases, and becomes a prominent player in vessel contractility hyperreactivity. Simply put, high blood sugar, by way of altered cell signaling in the VSM, causes blood vessels to contract and stays contracted. This is one mechanism which contributes to hypertension in T2DM.
When blood sugar levels are healthy, the VSM contractile state is regulated by the concentration of free calcium in the cell. Whenever an organism relies on ATP, there will be a lot of phosphate in the cell. Because of this, that system will have to develop mechanisms to keep calcium outside of the cell because the ensuing calcium phosphate would precipitate. This would immediately kill the cell. And so, small calcium influxes would then make for an attractive option for cell signaling – there’s a brief little evolutionary history on why calcium is a major focus of cell biology. Our cells have developed multiple ways for keeping intracellular calcium levels extremely low. Looking at the picture above as a guide, free calcium will bind with the protein calmodulin (CM) which will interact with myosin light chain kinase (MLCK). This interaction leads to the phosphorylation of myosin light chain (MLC) which ultimately results in VSM contraction. Relaxation involves dephosphorylation of MLC by way of MLC phosphatase (MLCP), and the removal of free calcium. The phosphorylation status of MLC is now considered a key concept for anything vasoconstriction-related.
Hyperglycemia upregulates the RhoA/ROCK signaling pathway that inhibits the activity of MLC phosphatase, thereby contributing to the contractile state of VSM (Su, 2013). There are other proteins involved in this pathway as well, whose function is also altered under hyperglycemia. CPI-17 is a notable one – it is a phosphorylation-dependent myosin phosphatase inhibitory protein, with high expression in the arteries (Su, 2013)
Here’s some western blot data depicting that CPI-17, both phosphorylated (CPI-17-P) and total, is upregulated in the smooth muscle of the aorta in db/db mice. db/db mice are regularly used to study the relationship between blood glucose and blood pressure as they display hyperglycemia, hypertension, and vascular dysfunction. Think of phosphorylated CPI-17 as being an “activated” form, which then inhibits myosin phosphatase, preventing the smooth muscle from relaxing.
As blood is pumped into the aorta, the aorta stretches (the systolic blood pressure). The aorta is very elastic – when stretched, it will recoil. This squeezes/pushes the blood downwards. When the aorta comes back to its original size, the pressure it experiences is the diastolic blood pressure. And so, you can imagine how higher CPI-17 (both phosphorylated and total), in the smooth muscle of the aorta would lead to an increase in blood pressure.
Here’s more western blot data, this time showing how CPI-17-P is dramatically increased in the mesenteric arteries of db/db mice. The mesenteric arteries are small blood vessels that branch off your aorta and connect to your digestive tract. Small resistance arteries like these contribute substantially to total peripheral resistance. When structural changes (like a decrease in lumen diameter) occur here, total peripheral resistance and thus blood pressure increases. This can be from inflammation, fibrosis, or a hyperactive sympathetic nervous system causing chronic vasoconstriction. This can be a vicious cycle in of itself – greater force on the walls of the blood vessel can be a stimulus for hypertrophy, triggering an inward remodeling response. The growth of the tunica media (middle layer) can also cause the vessel to build outwards, negatively affecting the elasticity of the vessel.
Khavandi et al. Nephrol Dial Transplant. 2009;24(2):361-369.
A stiff vessel is unable to adapt to changes in blood pressure as well, affecting systolic and diastolic values.
Interestingly, high volumes of food intake alone, independent of blood sugar, appears to have an incredible impact on the remodeling of the structure of the mesenteric arteries. This increased blood flow results in more stress on the vessel wall, resulting in a hypertrophic and outward remodeling response. The satiety effects of GLP-1 receptor agonists, I believe, is one of the mechanisms by which they show reductions in major adverse cardiovascular events – a topic covered here.
While there’s much more to explore on this topic, this at least gives a bit of insight (and hopefully a broader perspective) into the relationship between blood sugar and pressure. As I learn more, I’ll continue to expand on this topic.
Khavandi, K., Greenstein, A. S., Sonoyama, K., Withers, S., Price, A., Malik, R. A., & Heagerty, A. M. (2009). Myogenic tone and small artery remodelling: insight into diabetic nephropathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association – European Renal Association, 24(2), 361–369. https://doi.org/10.1093/ndt/gfn583
Su, W., Xie, Z., Liu, S., Calderon, L. E., Guo, Z., & Gong, M. C. (2013). Smooth muscle-selective CPI-17 expression increases vascular smooth muscle contraction and blood pressure. American journal of physiology. Heart and circulatory physiology, 305(1), H104–H113. https://doi.org/10.1152/ajpheart.00597.2012